Using a hypothetical scenario to assess public preferences for colorectal surveillance following screening-detected, intermediate-risk adenomas: annual home-based stool test vs. triennial colonoscopy

Background To assess public preferences for colorectal cancer (CRC) surveillance tests for intermediate-risk adenomas, using a hypothetical scenario. Methods Adults aged 45–54 years without CRC were identified from three General Practices in England (two in Cumbria, one in London). A postal survey was carried out during a separate study on preferences for different first-line CRC screening modalities (non- or full-laxative computed tomographic colonography, flexible sigmoidoscopy, or colonoscopy). Individuals were allocated at random to receive a pack containing information on one first-line test, and a paragraph describing CRC surveillance recommendations for people who are diagnosed with intermediate-risk adenomas during screening. All participants received a description of two surveillance options: annual single-sample, home-based stool testing (consistent with Faecal Immunochemical Tests; FIT) or triennial colonoscopy. Invitees were asked to imagine they had been diagnosed with intermediate-risk adenomas, and then complete a questionnaire on their surveillance preferences. Results 22.1 % (686/3,100) questionnaires were returned. 491 (15.8 %) were eligible for analysis. The majority of participants stated a surveillance preference for the stool test over colonoscopy (60.8 % vs 31.0 %; no preference: 8.1 %; no surveillance: 0.2 %). Women were more likely to prefer the stool test than men (66.7 % vs. 53.6 %; p = .011). The primary reason for preferring the stool test was that it would be done more frequently. The main reason to prefer colonoscopy was its superiority at finding polyps. Conclusions A majority of participants stated a preference for a surveillance test resembling FIT over colonoscopy. Future research should test whether this translates to greater adherence in a real surveillance setting

Identification of the growth arrest and DNA damage protein GADD34 in the normal human heart and demonstration of alterations in expression following myocardial ischaemia

Growth arrest and DNA damage protein 34 (GADD34) is a multifunctional protein upregulated in response to cellular stress and is believed to mediate DNA repair and restore protein synthesis. In the present study we have examined GADD34 immunoreactivity in human myocardial tissue at defined survival times following cardiac arrest and determined alterations in expression following ischaemia. In the normal human heart, GADD34 immunoreactivity was generally intense and present within most cells. GADD34 immunoreactivity was downregulated in tissue displaying ischaemic damage and remained intense in adjacent non-infarcted tissue. Unlike brain, GADD34 was not found to be upregulated in the peri-infarct zone. Cells displaying apoptotic changes were located in regions displaying reduced GADD34 immunoreactivity. In the brain, it is thought that GADD34 supports re-initiation of protein synthesis following ischaemia. Similarly, GADD34 may perform important functions in cardiac tissue in response to ischaemia

Mechanisms and Clinical Consequences of Vascular Calcification

Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health

Neutral proteases of human polymorphonuclear granulocytes: putative mediators of pulmonary damage.

Tissue proteolytic enzymes are currently believed to be critical to the pathogenesis of panacinar emphysema. Polymorphonuclear leukocytes (Polys) have several enzymes including elastase and cathepsin G in their azurophil granules. They have collagenase in their specific granules. We have found that this collagenase is doubly latent. It has the lysosomal type of latency that depends on the impermeability of the unit membrane that surrounds each specific granule. In addition it has a latency that is converted to activity by proteolytic enzymes. The cathepsin G of the azurophil granule is a potent activator of this latent collagenase once the collagenase is released from its membrane dependent latency. Thus latency of enzymes, the nature of the latency and accessibility of the latent enzymes to activating mechanisms must all be taken into account in any analysis of their contribution to pathogenesis of local lung disease. Equally important is that fact that polys are not a prominent cellular component of normal lung. Polys must be attracted to the lung by chemotactic peptides. These peptides must be released by the interaction of inflammatory stimuli, such as smoke particles, with complement components or they must be provided by other sources. The hypothesis that lung damage in panacinar emphysema is mediated by polys and their proteases is attractive and suggestive evidence supporting this is available. However, more evidence that takes into full account the cell biology of the proteases any poly turnover in the lung are needed to extend the hypothesis and to form a rational basis for therapeutic and prophylactic measures

Hearing-Aid Safety: A Comparison of Estimated Threshold Shifts for Gains Recommended by Nal-Nl2 and Dsl M[i/O] Prescriptions for Children

Objective: To investigate the predicted threshold shift associated with the use of nonlinear hearing aids fitted to the NAL-NL2 or the DSL m[i/o] prescription for children with the same audiograms. For medium and high input levels, we asked: (1) How does predicted asymptotic threshold shifts (ATS) differ according to the choice of prescription? (2) How does predicted ATS vary with hearing level for gains prescribed by the two prescriptions? Design: A mathematical model consisting of the modified power law combined with equations for predicting temporary threshold shift (Macrae, 1994b) was used to predict ATS. Study sample: Predicted threshold shift were determined for 57 audiograms at medium and high input levels. Results: For the 57 audiograms, DSL m[i/o] gains for high input levels were associated with increased risk relative to NAL-NL2. The variation of ATS with hearing level suggests that NAL-NL2 gains became unsafe when hearing loss \u3e 90 dB HL. The gains prescribed by DSL m[i/o] became unsafe when hearing loss \u3e 80 dB HL at a medium input level, and \u3e 70 dB HL at a high input level. Conclusion: There is a risk of damage to hearing for children using nonlinear amplification. Vigilant checking for threshold shift is recommended

Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

Polarisation of equine pregnancy outcome is associated with a maternal MHC class I allele

Identification of risk factors which are associated with severe clinical signs can assist in the management of disease outbreaks and indicate future research areas. Pregnancy loss during late gestation in the mare compromises welfare, reduces fecundity and has financial implications for horse owners. This retrospective study focussed on the identification of risk factors associated with pregnancy loss among 46 Thoroughbred mares on a single British stud farm, with some but not all losses involving equid herpesvirus-1 (EHV-1) infection. In a sub-group of 30 mares, association between pregnancy loss and the presence of five common Thoroughbred horse haplotypes of the equine Major Histocompatibility Complex (MHC) was assessed. This involved development of sequence specific, reverse transcriptase polymerase chain reactions and in several mares, EHV-1 specific, cytotoxic T lymphocyte activity. Of the 46 mares, 10 suffered late gestation pregnancy loss or neonatal foal death, five of which were EHV-1 positive. Maternal factors including age, parity, number of EHV-1 specific vaccinations and the number of days between final vaccination and foaling or abortion were not significantly associated with pregnancy loss. In contrast, a statistically significant association between the presence of the MHC class I B2 allele and pregnancy loss was identified, regardless of the fetus / foal’s EHV-1 status (p=0.002). In conclusion, this study demonstrated a significantly positive association between pregnancy loss in Thoroughbred mares and a specific MHC class I allele in the mother. This association requires independent validation and further investigation of the mechanism by which the mare’s genetic background contributes to pregnancy outcome