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YouTube as a social media platform plays an important role in sharing public views about a range of scientific topics such as parapsychology: an area of science committed to exploring the workings behind anomalous experiences or abilities. This qualitative study analyses how conversations about public perspectives of research into parapsychology, take place on YouTube. Reflective Thematic Analysis (RTA) is used to examine comments on the threads for two comparative films posted by two leading academics with opposing views. Three central themes have emerged: (i) Confirmation Bias; (ii) Laws of Nature, and (iii) Trashing the Holy Altars. Following on from this study, it would be beneficial to carry out a larger study with an additional social media platform for further in-depth analysis of public perceptions of parapsychology and how they are presented online. [ABSTRACT FROM AUTHOR]

Belief in life after death forms a key aspect of all major established religions, and even in individuals not overtly religious. These beliefs significantly influence their experiences and behaviours. Previous research has assessed afterlife beliefs in wider theoretical and empirical contexts including generic paranormal belief, religious beliefs, or belief in an afterlife as a coping mechanism against death anxiety. There are currently few measures directly examining individual differences in life after death beliefs. We designed the Survival Beliefs Questionnaire (SBQ) and assessed its psychometric properties in 297 adults. To assess its validity we also asked them to complete standard measures of paranormal and religious beliefs. The psychometric properties of our questionnaire were found to be excellent. There were significant positive correlations for scores on the SBQ with paranormal belief and religiosity, thus confirming its validity. In addition, the data revealed sex differences as females scored significantly higher than males on all three measures. A series of regressions (controlling for sex) were then conducted, initially with paranormal and religious questionnaires total scores, and then with their individual subscales. Total scores on both paranormal, and religious questionnaires made significant contributions to SBQ total score. When assessing the contribution of the subscales of the paranormal and religious scales, only the paranormal subscale of spiritualism made a significant contribution to SBQ scores. In sum, we have created a novel questionnaire to explore individual differences in life after death beliefs which can be used in future studies to assess sociopsychological characteristics and resulting behaviours associated with such beliefs. [ABSTRACT FROM AUTHOR]

We report on a systematic review of evaluations of education voucher programs in developing countries. Extensive searching identified two studies that met inclusion criteria—one examining the Colombia PACES program and the other evaluating the Quetta, Pakistan Urban Fellowship program. Both programs increased private school enrollment among the countries’ poorest income groups, thus probably improving equity. The Pakistan program resulted in girls being educated for less than it would have cost for the government to create public school spaces, while the Colombia program cost more, but will most likely prove cost-effective in terms of long-term economic gains. More rigorous research in developing country contexts is necessary to determine whether the gains from these two programs can be replicated and enhanced. [ABSTRACT FROM AUTHOR]

Due to evidence linking education and development, funding has been invested in interventions relevant to getting youth into school and keeping them there. This article reports on a systematic review of impact studies of these school enrollment interventions. Reports were identified through electronic searches of bibliographic databases and other methods. To be eligible, studies (1) assessed impact on primary or secondary school enrollment outcomes; (2) used a rigorous design; (3) were conducted in a low- or middle-income nation; (4) included at least one quantifiable measure of enrollment or related outcomes; (5) were available before December 2009; and (6) included data on participants post-1990. A coding instrument extracted data on study characteristics from each report. Standardized mean difference effect sizes were computed for the first effect reported. The sample includes 73 evaluations. The average effect size was positive across all outcomes. However, the results varied. Studies that focused on building new schools and other infrastructure interventions reported the largest average effects. [ABSTRACT FROM PUBLISHER]

Mitochondrial data have traditionally been used in reconstructing a variety of species phylogenies. The low rates of recombination and thorough characterization of mitochondrial data across vertebrate species make it a particularly attractive phylogenetic marker. The relatively low number of fully sequenced mammal genomes and the lack of extensive sampling within Superorders have posed a serious problem for reaching agreement on the placement mammal species. The use of mitochondrial data sequences from large numbers of mammals could serve to circumvent the taxon-sampling deficit. Here we assess the suitability of mitochondrial data as a phylogenetic marker in mammal phylogenetics. MtDNA datasets of mammal origin have been filtered as follows: (i) we have sampled sparsely across the phylogenetic tree, (ii) we have constrained our sampling to genes with high taxon coverage, (iii) we have categorised rates across sites in a phylogeny independent manner and have removed fast evolving sites, and (iv), we have sampled from very shallow divergence times to reduce phylogenetic conflict. However, topologies obtained using these filters are not consistent with previous studies and are discordant across different genes. Individual mitochondrial genes, and indeed all mitochondrial genes analysed as a supermatrix, resulted in poor resolution of the species phylogeny. Overall, our study highlights the limitations of mitochondrial data, not only for resolving deep divergences and but also for shallow divergences in the mammal phylogeny. [ABSTRACT FROM AUTHOR]

Background Placental mammals display a huge range of life history traits, including size, longevity, metabolic rate and germ line generation time. Although a number of general trends have been proposed between these traits, there are exceptions that warrant further investigation. Species such as naked mole rat, human and certain bat species all exhibit extreme longevity with respect to body size. It has long been established that telomeres and telomere maintenance have a clear role in ageing but it has not yet been established whether there is evidence for adaptation in telomere maintenance proteins that could account for increased longevity in these species. Results Here we carry out a molecular investigation of selective pressure variation, specifically focusing on telomere associated genes across placental mammals. In general we observe a large number of instances of positive selection acting on telomere genes. Although these signatures of selection overall are not significantly correlated with either longevity or body size we do identify positive selection in the microbat species Myotis lucifugus in functionally important regions of the telomere maintenance genes DKC1 and TERT, and in naked mole rat in the DNA repair gene BRCA1. Conclusion These results demonstrate the multifarious selective pressures acting across the mammal phylogeny driving lineage-specific adaptations of telomere associated genes. Our results show that regardless of the longevity of a species, these proteins have evolved under positive selection thereby removing increased longevity as the single selective force driving this rapid rate of evolution. However, evidence of molecular adaptations specific to naked mole rat and Myotis lucifugus highlight functionally significant regions in genes that may alter the way in which telomeres are regulated and maintained in these longer-lived species. [ABSTRACT FROM AUTHOR]

Background: Currently available methods for diagnosis and staging of prostate cancer lack the sensitivity to distinguish between patients with indolent prostate cancer and those requiring radical treatment. Alterations in key adherens (AJ) and tight junction (TJ) components have been hailed as potential biomarkers for prostate cancer progression but the majority of research has been carried out on individual molecules. Objective: To elucidate a panel of biomarkers that may help distinguish dormant prostate cancer from aggressive metastatic disease. Methods: We analysed the expression of 7 well known AJ and TJ components in cell lines derived from normal prostate epithelial tissue (PNT2), non-invasive (CAHPV-10) and invasive prostate cancer (LNCaP, DU145, PC-3) using gene expression, western blotting and immunofluorescence techniques. Results: Claudin 7, α –catenin and β-catenin protein expression were not significantly different between CAHPV-10 cells and PNT2 cells. However, in PC-3 cells, protein levels for claudin 7, α –catenin were significantly down regulated (−1.5 fold, p = <.001) or undetectable respectively. Immunofluoresence showed β-catenin localisation in PC-3 cells to be cytoplasmic as opposed to membraneous. Conclusion: These results suggest aberrant Claudin 7, α – and β-catenin expression and/or localisation patterns may be putative markers for distinguishing localised prostate cancer from aggressive metastatic disease when used collectively. [ABSTRACT FROM AUTHOR]

Background: Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages. Results: Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1. Conclusion: Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases. [ABSTRACT FROM AUTHOR]

In this study scanning near-field optical microscopy (SNOM) has been utilised in conjunction with quantum dot labelling to interrogate the biomolecular composition of cell membranes. The technique overcomes the limits of optical diffraction found in standard fluorescence microscopy and also yields vital topographic information. The technique has been applied to investigate cell-cell adhesion in human epithelial cells. This has been realised through immunofluorescence labelling of the cell-cell adhesion protein E-cadherin. Moreover, a dual labelling protocol has been optimised to facilitate a comparative study of the adhesion mechanisms and the effect of aberrant adhesion protein expression in both healthy and cancerous epithelial cells. This study reports clear differences in the morphology and phenotype of healthy and cancerous cells. In healthy prostate epithelial cells (PNT2), E-cadherin was predominantly located around the cell periphery and within filopodial extensions. The presence of E-cadherin appeared to be enhanced when cell-cell contact was established. In contrast, examination of metastatic prostate adenocarcinoma cells (PC-3) revealed no E-cadherin labelling around the periphery of the cells. This lack of functional E-cadherin in PC-3 cells coincided with a markedly different morphology and PC-3 cells were not found to form close cell-cell associations with their neighbours. We have demonstrated that with a fully optimised sample preparation methodology, multiplexed quantum dot labelling in conjunction with SNOM imaging can be successfully applied to interrogate biomolecular localisation within delicate cellular membranes. [ABSTRACT FROM AUTHOR]

Background: Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the mammalia are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of mammalia. Results: We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality. Conclusion: Our in silico analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the mammalia and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene. [ABSTRACT FROM AUTHOR]

Abstract: Background: Angiogenesis plays an essential role in the growth and metastatic development of tumours. Recent in vitro studies have reported bisphosphonates as having anti-angiogenic properties. They have been shown to inhibit proliferation, induce apoptosis and decrease capillary-like tube formation, but often the in vitro concentrations and dosing schedules used do not reflect drug pharmacokinetics or clinical dosing regimens. Materials and methods: Human umbilical vein endothelial cells were exposed to physiologically relevant doses of the bisphosphonate ibandronate, mimicking the clinical administration of oral ibandronate (1 h daily dosing over 8 days at concentrations ranging from 1–10 μM). Cellular growth characteristics were then assessed. Results: Low-dose ibandronate (1.25–2 μM) significantly reduced endothelial cell growth, while 2 μM ibandronate also significantly reduced capillary-like tube formation and increased apoptosis of endothelial cells compared to untreated cells. There was no significant difference in activity with doses above 2 μM. However, inhibiting bFGF stimulated cell growth increased VEGF expression. Conclusion: This work has demonstrated that repeated low-dose drug administration (metronomic therapy) of ibandronate has certain anti-angiogenic properties by inhibiting the stimulatory effects of bFGF. However targeting the inhibition of bFGF alone is unlikely to be a successful approach for completely inhibiting angiogenesis due to the interplay between bFGF and VEGF. [Copyright &y& Elsevier]

Abstract: The TRPA1 receptor is a member of the ankyrin family and is found in both spinal and trigeminal neurones. There is evidence to suggest that this receptor may be a sensor of noxious thermal stimuli in normal animals. After nerve injury, TRPA1 shows increased expression in uninjured axons, and has been implicated in the development and maintenance of hyperalgesia. We examined expression of TRPA1 in lingual nerve neuromas and investigated any potential correlation with the presence or absence of symptoms of dysaesthesia. Thirteen neuroma-in-continuity specimens were obtained from patients undergoing repair of a lingual nerve that had previously been damaged during lower third molar removal. Visual analogue scales (VAS) were used to record the degree of pain, tingling and discomfort. Tissue was processed for indirect immunofluorescence and the percentage area of PGP 9.5-immunoreactive neuronal tissue also labelled for TRPA1 was quantified. No significant difference between levels of TRPA1 in neuromas from patients with or without symptoms of dysaesthesia and no relationship between TRPA1 expression and VAS scores for pain, tingling or discomfort were observed. TRPA1 expression and the time after initial injury that the specimen was obtained also showed no correlation. These data show that TRPA1 is expressed in lingual nerve neuromas, but, it appears that, at this site, TRPA1 does not play a principal role in the development of neuropathic pain. [Copyright &y& Elsevier]

Purpose. Zoledronic acid is widely accepted as the treatment of choice for a number of cancers which metastasise to bone and is the only bisphosphonate licensed for the treatment of prostate cancer. However, drug related nephrotoxicity, although rare, does pose a significant complication when using zoledronic acid. Prostate cancer patients are generally older than 65 years of age and already exhibit some form of impaired renal function. Thus, for prostate cancer patients who are unable to tolerate zoledronic acid there is a need for an alternative bisphosphonate. One possibility could be ibandronate which is also a potent third generation, nitrogen-containing bisphosphonate and is an attractive choice for some patients due to the fact it is available in both intravenous and oral preparations. Methods. This article reviews the current published literature regarding the use of ibandronate in the treatment of metastatic prostate cancer. Results. Preliminary data emerging from small Phase II studies suggests ibandronate may provide a therapeutic alternative for the treatment of metastatic prostate cancer when zoledronic acid is deemed unsuitable. Conclusion. Further in vivo research with ibandronate in prostate cancer is urgently needed in order to elucidate whether this bisphosphonate may play a role in the treatment and palliative management of metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

Bisphosphonates and chemotherapy have increasingly gained favour in the treatment of metastatic hormone resistant prostate cancer. We investigated whether zoledronic acid, at a concentration found at the bone, would enhance the anti-tumour activity of docetaxel in the hormone resistant prostate cancer cell line PC-3. Cells were exposed to zoledronic acid (1 mM) in combination or in sequence with docetaxel (3 nM). Cell viability, apoptosis and markers for inhibition of the mevalonate pathway were analyzed 48 or 72 hours after drug treatment. Reduction in cell viability and increased apoptosis levels were most pronounced with single agent zoledronic acid. Western blot analysis showed an overall reduction in the proliferation marker Mini chromosome maintenance protein 2 (MCM2) and reduction in caspase-3 precursor for all drug treatments and a marked reduction in Rho A levels with single agent zoledronic acid and zoledronic acid-docetaxel sequence. This study highlights the potency of zoledronic acid, when used at concentrations similar to those found at the bone, in reducing cell viability and causing apoptosis. Clinically, these findings suggest that in patients with bone metastases due to hormone resistance prostate cancer, who are not fit enough for systemic chemotherapy, single agent zoledronic acid may have a direct effect on viability of prostate cancer epithelial cells. [ABSTRACT FROM AUTHOR]

Abstract: The sensitivity of any mutational assay is determined by the level at which spontaneous mutations occur in the corresponding untreated controls. Establishing the type and frequency at which mutations occur naturally within a test system is essential if one is to draw scientifically sound conclusions regarding chemically induced mutations. Currently, mutation-spectra analysis is laborious and time-consuming. Thus, we have developed iMARS, a comprehensive mutation-spectrum analysis package that utilises routinely used methodologies and visualisation tools. To demonstrate the use and capabilities of iMARS, we have analysed the distribution, types and sequence context of spontaneous base substitutions derived from the cII gene mutation assay in transgenic animals. Analysis of spontaneous mutation spectra revealed variation both within and between the transgenic rodent test systems Big Blue Mouse, MutaMouse and Big Blue Rat. The most common spontaneous base substitutions were G:C→A:T transitions and G:C→T:A transversions. All Big Blue Mouse spectra were significantly different from each other by distribution and nearly all by mutation type, whereas the converse was true for the other test systems. Twenty-eight mutation hotspots were observed across all spectra generally occurring in CG, GA/TC, GG and GC dinucleotides. A mutation hotspot at nucleotide 212 occurred at a higher frequency in MutaMouse and Big Blue Rat. In addition, CG dinucleotides were the most mutable in all spectra except two Big Blue Mouse spectra. Thus, spontaneous base-substitution spectra showed more variation in distribution, type and sequence context in Big Blue Mouse relative to spectra derived from MutaMouse and Big Blue Rat. The results of our analysis provide a baseline reference for mutation studies utilising the cII gene in transgenic rodent models. The potential differences in spontaneous base-substitution spectra should be considered when making comparisons between these test systems. The ease at which iMARS has allowed us to carry out an exhaustive investigation to assess mutation distribution, mutation type, strand bias, target sequences and motifs, as well as predict mutation hotspots provides us with a valuable tool in helping to distinguish true chemically induced hotspots from background mutations and gives a true reflection of mutation frequency. [Copyright &y& Elsevier]

INTRODUCTION: Acid, a principal component of refluxate, may contribute to the neoplastic progression of Barrett's esophagus. Brief acid exposurein vivoandin vitrohas been shown to increase cell proliferation. The mechanisms underlying the hyperproliferative response are not well elucidated but may include alterations in Na+–H+ exchanger activity and MAPK signaling pathways.OBJECTIVE: To ascertain the effects of pulsatile acid exposure on gene expression in a Barrett's adenocarcinoma cell line (SEG-1).METHODS: SEG-1 cells were exposed to either acidified DMEM at pH 3.5 (0.1 M hydrochloric acid) or pH 7.4 (control) for 20 min followed by neutralization of the medium. Total RNA was extracted before acid exposure and over a 10-h time course (0.5, 2, 4, 6, 8, and 10 hours) and hybridized to Affymetrix human U133A oligonucleotide arrays. Data were analyzed using the Affymetrix statistical expression algorithms. Only alterations in gene expression that were≥2 and≤−2 fold were studied further and a subset was further investigated by reverse transcription polymerase chain reaction (RT-PCR) and densitometry. Apoptosis was assayed in SEG-1 cells by western blot for cleaved caspase 3 and an apoptosis ELISA assay.RESULTS: Changes in expression were identified for 138 genes. Analysis of gene function identified immediate downregulation of genes associated with apoptosis and early upregulation of genes associated with proliferation. The gene expression profiles suggest that MAPK pathways may be involved and suppression of apoptosis may occur via p53-dependent mechanisms.CONCLUSION: Microarray analysis of gene expression changes in a Barrett's adenocarcinoma cell line has identified cellular pathways that may be disrupted following acid exposure. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of tilt table incline and knee flexion angle on the degree of weight bearing and forces exerted across the supporting straps. Design: A quantitative and exploratory study to investigate the effects of a mechanical procedure. Setting: Physiotherapy gymnasium. Subjects: Twelve healthy subjects (9 female, 3 male) aged 22-45 years. Interventions: Subjects stood on a tilt table, on two occasions, with simulated contractures of 10° and 40° knee flexion. Nine tilt angles, between 10° and 90°, were maintained for 1 minute each in random order. Main outcome measures: Force was recorded from single-point load cells placed under the feet, and at knee and chest straps. Results: The degree of simulated knee contracture (10° or 40°) influenced the distribution of forces at different recording sites. Weight bearing increased with table incline and was significantly less with the 40° than the 10° knee angle (p < 0.001). Conversely, forces across the knee straps were systemically higher with the 40° knee angle (p < 0.0001). The effects were accentuated by greater body weight. Forces across the chest strap also increased with tilt and were significantly larger with the 40° knee angle (p < 0.05). Conclusions: The relationships between table incline, angle of knee flexion and distribution of forces generated during tilt table standing have been quantified and described. Standing with flexed knees involved less weight bearing under the feet and greater force exerted across the supporting straps. These effects were more pronounced at the higher knee angle and with greater body weight, and could be modified by reducing table incline. [ABSTRACT FROM AUTHOR]

Examines the relationship between narcissistic personality and paranormal belief in Great Britain. Definition of the paranormal beliefs; Device used in measuring level of paranormal belief; Significance of paranormal belief scale in personality assessment.

Background: Bacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo. Results: The attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERT2Apcflx/flx and BlgCreBrca2flx/flp53flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50–95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 106 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals. Conclusions: In summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation. [ABSTRACT FROM AUTHOR]

Background: Genes that encode proteins associated with sperm competition, fertilization, and sexual conflicts of interest are often among the most rapidly evolving parts of animal genomes. One family of sperm-expressed genes (Zp3r, C4bpa) in the mammalian gene cluster called the regulator of complement activation (RCA) encodes proteins that bind eggs and mediate reproductive success, and are therefore expected to show high relative rates of nonsynonymous nucleotide substitution in response to sexual selection in comparison to other genes not involved in gamete binding at fertilization. We tested that working hypothesis by using phylogenetic models of codon evolution to identify episodes of diversifying positive selection. We used a comparative approach to quantify the evidence for episodic diversifying selection acting on RCA genes with known functions in fertilization (and sensitivity to sexual selection), and contrast them with other RCA genes in the same gene family that function in innate immunity (and are not sensitive to sexual selection). Results: We expected but did not find evidence for more episodes of positive selection on Zp3r in Glires (the rodents and lagomorphs) or on C4BPA in Primates, in comparison to other paralogous RCA genes in the same taxon, or in comparison to the same orthologous RCA gene in the other taxon. That result was not unique to RCA genes: we also found little evidence for more episodes of diversifying selection on genes that encode selective sperm-binding molecules in the egg coat or zona pellucida (Zp2, Zp3) in comparison to members of the same gene family that encode structural elements of the egg coat (Zp1, Zp4). Similarly, we found little evidence for episodic diversifying selection acting on two other recently discovered genes (Juno, Izumo1) that encode essential molecules for sperm–egg fusion. Conclusions: These negative results help to illustrate the importance of a comparative context for this type of codon model analysis. The results may also point to other phylogenetic contexts in which the effects of selection acting on these fertilization proteins might be more readily discovered and documented in mammals and other taxa. [ABSTRACT FROM AUTHOR]

BACKGROUND: The adult mammalian heart has little regenerative capacity after myocardial infarction (MI), whereas neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. METHODS AND RESULTS: Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA (miRNA) expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and noncoding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two-thirds of each of the messenger RNAs, long noncoding RNAs, and miRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR-451a, and miR-6240 showed evidence of functional conservation in human cardiomyocytes. CONCLUSIONS: The sets of messenger RNAs, miRNAs, and long noncoding RNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period. [ABSTRACT FROM AUTHOR]

Development of questionnaires to measure patient preferences for intranasal corticosteroids in patients with allergic rhinitis. For example, whilst a smaller proportion of participants using OLO/MOM reported more than 1 AR treatment in the past 12 months compared to participants using AZE/FLU (49% for OLO/MOM; 75.9% for AZE/FLU), the argument that patients had to be dissatisfied with their previous treatment and thus more likely to suffer severe allergic rhinitis (AR) to be prescribed AZE/FLU, somehow skewing the results is an interesting hypothesis which is not supported by the subgroup analysis observations. Simon Fifer, Lili Toh Community and Patient Preference Research (CaPPRe) Pty Ltd, Sydney, New South Wales, Australia Correspondence: Simon Fifer, Community and Patient Preference Research (CaPPRe), Level 20, 25 Bligh Street, Sydney, New South Wales, 2000, Australia, Tel +61 403 862 091, Email [email protected] View the original paper by Dr Fifer and colleagues This is in response to the Letter to the Editor Dear editor Thank you for the opportunity to respond to the Letter to the Editor regarding our manuscript titled "Patient Satisfaction and Sensory Attributes of Nasal Spray Treatments of Olopatadine Hydrochloride/Mometasone Furoate Monohydrate and Azelastine Hydrochloride/Fluticasone Propionate for Allergic Rhinitis in Australia - An Observational Real-World Clinical Study". [Extracted from the article]

Background: The concept of control has long been suggested as a central factor in eating disorder (ED) aetiology. The concept is now so mainstream that it risks being used in a potentially reductionist, stigmatising or otherwise harmful manner. In this paper, we explore and discuss our positions on the use of control-related terminology for EDs. Methods: The authors of this auto-ethnographic position paper include academic researchers, individuals with lived experience and clinicians (not mutually exclusive). In sharing our experiences and observations, we aim to raise awareness of the wider impacts that control framing can have on ED perceptions, treatment, recovery and individuals' lived experience. Results: We argue that although control can play a role in some ED experiences, an overemphasis upon this factor to the exclusion of other conceptualisations is not beneficial. Conclusions: To mitigate against pathologisation of an individual, it is important to challenge a discourse that can lead to EDs being perceived as something 'wrong' with the individual, rather than a consequence of life events or other environmental influences. We identify priorities for the future for researchers, clinicians, policy makers and the wider public. Plain English summary: Control has often been described as a central factor within Eating Disorders (EDs). Whilst control can play a role in ED experiences, we argue that overemphasis upon this factor can result in other important factors being overlooked. For many individuals, EDs are the consequence of life events and/or other environmental influences. With this in mind, discourse which overemphasises control (e.g., rather than coping) can inaccurately portray EDs as something 'wrong' with the individual. It is important to challenge this discourse to encourage more appropriate perceptions of EDs. In turn, this could improve understanding and treatment of EDs, reduce stigma, and promote recovery. [ABSTRACT FROM AUTHOR]

Purpose: Combination intranasal corticosteroid and antihistamine sprays are a first-line treatment option for allergic rhinitis (AR), of which Azelastine Hydrochloride and Fluticasone Propionate nasal spray (AZE/FLU; Dymista®), and Olopatadine Hydrochloride and Mometasone Furoate Monohydrate nasal spray (OLO/MOM; Ryaltris®) are currently registered in Australia. As it is not known how patients value treatment attributes of current combination nasal sprays, this observational, real-world clinical study aimed to understand patients' satisfaction with, and importance of, treatment attributes of OLO/MOM and AZE/FLU using an Anchored Best-Worst Scaling (ABWS) exercise. Participants and Methods: Four hundred and twenty-six adults in Australia with moderate to severe AR using either OLO/MOM or AZE/FLU completed an online survey incorporating an ABWS with 11 domains: 7 sensory (immediate taste of medication, aftertaste of medication, smell of medication, irritation to your nose, urge to sneeze, dripping out your nose/down your throat, dryness of your nose/throat) and 4 treatment-related (convenience, fast acting, duration of effect, and AR symptom control). The ABWS involved rescaling individual BWS scores using anchored ratings (0– 10) for most and least satisfied/important domains to create a total satisfaction index (TSI) (0– 100) to be compared across groups. Statistical comparisons were completed using ANOVA (TSI) and MANOVA (individual domains). Results: Participants using OLO/MOM (M = 68.26, SE = 1.39) had significantly higher TSI than participants using AZE/FLU (M=62.78, SE = 0.70) (p < 0.001), significantly higher satisfaction on 7 of 11 domains and regarded 8 of 11 domains as significantly more important compared to participants using AZE/FLU (all p < 0.05). Preferred domains were predominantly sensory attributes. Conclusion: Current findings showed that participants using OLO/MOM were more satisfied with their overall treatment compared to participants using AZE/FLU, particularly with sensory attributes, thus highlighting the suitability of OLO/MOM for people with AR who value sensory attributes. Prescribers of AR treatments are encouraged to discuss treatment attributes with patients to facilitate shared decision-making. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Understanding Why Some Ethnic Minority Patients Evaluate Medical Care More Negatively Than White Patients," by N. Mead and M. Roland, published in the September 16, 2009 issue.

Assessment of genetic toxicity and/or carcinogenic activity is an essential element of chemical screening programs employed to protect human health. Dose-response and gene mutation data are frequently analysed by industry, academia and governmental agencies for regulatory evaluations and decision making. Over the years, a number of efforts at different institutions have led to the creation and curation of databases to house genetic toxicology data, largely, with the aim of providing public access to facilitate research and regulatory assessments. This article provides a brief introduction to a new genetic toxicology portal called Mutation Analysis Informatics Tools (MutAIT) (www.mutait.org) that provides easy access to two of the largest genetic toxicology databases, the Mammalian Gene Mutation Database (MGMD) and TransgenicDB. TransgenicDB is a comprehensive collection of transgenic rodent mutation data initially compiled and collated by Health Canada. The updated MGMD contains approximately 50 000 individual mutation spectral records from the published literature. The portal not only gives access to an enormous quantity of genetic toxicology data, but also provides statistical tools for dose-response analysis and calculation of benchmark dose. Two important R packages for dose-response analysis are provided as webdistributed applications with user-friendly graphical interfaces. The 'drsmooth' package performs dose-response shape analysis and determines various points of departure (PoD) metrics and the 'PROAST' package provides algorithms for dose-response modelling. The MutAIT statistical tools, which are currently being enhanced, provide users with an efficient and comprehensive platform to conduct quantitative dose-response analyses and determine PoD values that can then be used to calculate human exposure limits or margins of exposure. [ABSTRACT FROM AUTHOR]

Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy. [ABSTRACT FROM AUTHOR]

Despite the contribution of unpaid carers to society in Wales, there is a lack of understanding of the true extent of unpaid carers, no routinely available data to understand the impact of caring on their own health and wellbeing, nor the longer-term effect on educational outcomes and employment perspectives. Such information is needed to help inform actions to reduce the harms within the Welsh Government's recovery plan, Leading Wales Out of the Coronavirus Pandemic , and also to inform the aspirations within the national Well-being of Future Generations (Wales) Act and the Social Services and Well Being (Wales) Act 2014. We aimed to identify an e-cohort of unpaid carers through routine health and administrative data in Wales. We validated a list of Read Codes to identify individuals recorded as unpaid carers in Wales who accessed NHS primary care services since Jan 1, 2010 until Oct 10, 2020, from the Welsh Longitudinal General Practice Dataset in the Secure Anonymised Information Linkage (SAIL) Databank. We then linked the e-cohort with primary care records to identify entries, diagnoses, or prescriptions for depression or anxiety symptoms within 1 year before they first appeared in the e-cohort. This study is exempt from consent due to the anonymised nature of the databank. The independent Information Governance Review Panel approved this study. 68 457 unpaid carers were identified via the initial scan and 94% (n=64 656) of those had full demographic information. We also included individuals (n=5009) who self-reported as unpaid carers in National Survey for Wales. Of them, 65% (n=41 999) of carers were female and 24% (n=15 581) were aged 55–64 years as of their first appeared in the e-cohort. 1% (n=918) of carers were younger than 16 years and 6% (n=3688) were older than 85 years. At least 9% (n=5646) of the unpaid carers had depression or anxiety, or both, while providing care. Our study creates a unique and reproducible e-cohort that enables rapid and better understanding of unpaid carers' health needs in Wales (eg, depression or anxiety). With ongoing work to include more routine datasets, including carers' assessment, it will allow privacy-protected analysis to support initiatives for carers (eg, carers' vaccine uptake during the pandemic). Despite the efforts of pulling together a comprehensive code list, there are systematic differences in recording non-health patient information in practice. This research was funded through Public Health Wales. [ABSTRACT FROM AUTHOR]

Microsurgical repair of transected peripheral nerves is compromised by the formation of scar tissue and the development of a neuroma, thereby limiting the success of regeneration. The aim of this study was to quantify histomorphometrically the structural changes in neural tissue that result from repair, and determine the effect of mannose-6-phosphate (M6P), a scar-reducing agent previously shown to enhance regeneration. In anaesthetised C57-black-6 mice, the left sciatic nerve was sectioned and repaired using four epineurial sutures. Either 100 μL of 600 m m M6P (five animals) or 100 μL of phosphate-buffered saline (placebo controls, five animals) was injected into and around the nerve repair site. A further group acted as sham-operated controls. After recovery for 6 weeks, the nerve was harvested for analysis using light and electron microscopy. Analysis revealed that when compared with sham controls, myelinated axons had smaller diameters both proximal and distal to the repair. Myelinated axon counts, axonal density and size all decreased across the repair site. There were normal numbers and densities of non-myelinated axons both proximal and distal to the repair. However, there were more Remak bundles distal to the repair site, and fewer non-myelinated axons per Remak bundle. Application of M6P did not affect any of these parameters. [ABSTRACT FROM AUTHOR]

Abstract: We have determined the effect of applying Mannose-6-Phosphate (M6P), a scar reducing agent, to a site of sciatic nerve repair. In anaesthetised C57-Black-6 mice, the left sciatic nerve was sectioned and repaired using 4 epineurial sutures. Either 100μl of 600mM Mannose-6-Phosphate (29 animals), or 100μl of phosphate buffered saline as a placebo control (29 animals), was injected into and around the nerve repair site. A further group acted as sham-operated controls. After 6 or 12weeks of recovery the extent of regeneration was assessed electrophysiologically and the percentage area of collagen staining at the repair site was analysed using picrosirius red and image analysis. Gait analysis was undertaken pre-operatively and at 1, 3, 6, 9 and 12weeks postoperatively, to assess functional recovery. At 6weeks the compound action potentials recorded from the regenerated nerves in the M6P group were significantly larger than in the placebo controls (P=0.015), and the conduction velocities were significantly faster (P=0.005), but there were no significant differences between these groups at 12weeks. Gait analysis suggested better early functional recovery in the M6P group. In both repair groups there was a significant reduction in collagen staining between 6 and 12weeks, suggestive of scar remodelling. We conclude that the normal scar remodelling process aids long term recovery in repaired nerves. Administration of 600mM M6P to the nerve repair site enhances nerve regeneration and functional recovery in the early stages, and may lead to improved outcomes. [Copyright &y& Elsevier]

During the pandemic healthcare faced great pressure on the availability of protective equipment. This paper describes the entire novel innovative process of design optimisation, production and deployment of face-visors to NHS frontline workers during SARS-CoV-2 pandemic. The described innovative journey spans collaboration between clinicians and academic colleagues for design to the implementation with industry partners of a face-visor for use in a healthcare setting. It identifies the enablers and barriers to development along with the strategies employed to produce a certified reusable, adjustable, high volume and locally produced face-visor. The article also explores aspects of value, scalability, spread and sustainability all of which are essential features of innovation. [ABSTRACT FROM AUTHOR]

Background: In 2004 an allocation formula for primary care services was introduced in England and Wales so practices would receive equitable pay. Modifications were made to this formula to enable local health authorities to pay practices. Similar pay formulae were introduced in Scotland and Northern Ireland, but these are unique to the country and therefore could not be included in this study. Objective: To examine the extent to which the Global Sum, and modifications to the original formula, determine practice funding. Methods: The allocation formula determines basic practice income, the Global Sum. We compared practice Global Sum entitlements using the original and the modified allocation formula calculations. Practices receive an income supplement if Global Sum payments were below historic income in 2004. We examined current overall funding levels to estimate what the effect will be when the income supplements are removed. Results: Virtually every Welsh and English practice (97%) received income supplements in 2004. Without the modifications to the formula only 72% of Welsh practices would have needed supplements. No appreciable change would have occurred in England. The formula modifications increased the Global Sum for 99.5% of English practices, while it reduced entitlement for every Welsh practice. In 2008 Welsh practices received approximately £6.15 (9%) less funding per patient per year than an identical English practice. This deficit will increase to 11.2% when the Minimum Practice Income Guarantee is abolished. Conclusions: Identical practices in different UK countries do not receive equitable pay. The pay method disadvantages Wales where the population is older and has higher health needs. [ABSTRACT FROM AUTHOR]

The article presents a study on the frequent prevalence of angina among coronary artery disease (CAD) patients in general care practices in Australia by the Coronary Artery Disease in General Practice (CADENCE) Study. It notes that limited awareness of clinicians on the angina burden of patients is the most important factor in angina prevalence. Moreover, it concludes that performance measurement and health practice feedbacks can improve clinical care and avoid angina recurrent prevalence.

Background: Kidney transplant recipients with active BK virus (BKV) replication are generally treated with reduction in immunosuppression to allow a successful immune response against the virus. Methods: We inadvertently administered Campath to two patients with BKV viruria, and one patient with BKV nephropathy, since allograft biopsies showed severe tubulitis or intimal arteritis, and results of PCR and in situ hybridization were not available at the time of therapeutic intervention. Results: Increased viral replication was observed, but not uniformly in all cases, and follow-up biopsies showed nephropathy in one additional case. Extra-renal dissemination did not occur. With subsequent reduction of immunosuppression or antiviral therapy, it was still possible to obtain clearance of viremia in all cases. Serum creatinine fell transiently after Campath in one patient; however, at one yr post-treatment all had increased levels over baseline. One graft was lost to persistent acute rejection that led to interstitial fibrosis and tubular atrophy. Conclusion: These cases suggest that Campath treatment does not (i) irreversibly deplete cells believed to be important in mounting an immune response against BKV, or (ii) preclude subsequent eradication of viral DNA from the blood. [ABSTRACT FROM AUTHOR]

Background. It is known that the age of transfused blood is a risk factor for the development of multiple organ failure in surgical patients. However, the character of hemorrheological changes in stored blood as well as the time when they appear remains disputable. We assumed that blood storage was accompanied by a progressive decrease of RBC deformability and rheological disorders. The degree of rheological disturbances should be directly proportional to the number of RBC with altered geometry.Materials and methods. Nine packages of RBC kept in adenine saline solution were examined from the 5th to the 42nd day of storage. RBC deformability index (DI) was determined by micropore filtration technique. RBC shape was estimated by means of scanning electron microscopy. Blood clotting time was measured by Sonoclot coagulation analyzer.Results. Significant alterations of RBC shape started at the second week of storage and progressed during the rest of the storage period. RBC shape changes were accompanied by progressive decrease in DI and increase in hemolysis and acidosis. The correlation index between the percentage of abnormally shaped RBC and DI was −0.81 (P = 0.0258). Blood clotting progressively decreased after 2 weeks of storage, probably due to the exhaustion of some procoagulant plasma factors.Conclusions. Serious hemorrheological disorders, including the decrease in RBC deformability secondary to shape abnormalities, acidosis, and the decrease of blood clotting, start already at the second week of storage and progress up to the end of the storage period. Transfusion of packed RBC older than 7 days may contribute to hemorrheological disorders in critically ill patients. [Copyright &y& Elsevier]

The internal stress states of Optimized ZIRLO (OPZ) samples are evaluated post-quenching from increasing temperatures to determine the role of chromium coatings, oxidation, and microstructural reorienting on internal stress state. Before substantial oxide development (under 700 °C), uncoated tubular samples freely expand and do not accumulate significant global internal stress. As a stable, passivizing oxide develops (700–900 °C), a complex stress state develops with both the interior and exterior oxides in hoop compression. The internal tensile stress increases until the sample fully oxides, and biaxial stress is released through tortoiseshell-like cracking mechanisms. When a chromium coating is introduced, the initial stress states at low temperatures are higher than the uncoated samples due to Cr-coating application techniques and material differences between Cr and OPZ. At higher temperatures (700–1100 °C), the Cr-coated samples undergo a much simpler stress state than the uncoated samples due to the tensile hoop stress state of the Cr-coating caused by differing thermal expansion and the compressive state of the internal oxide caused by a Pilling-Bedworth ratio > 1. The subsequent film cracking mechanisms also differ from the uncoated samples. The smoother stress state experienced by the Cr-coated vs uncoated OPZ samples allows the Cr-coated samples to maintain the circular geometry that is vital to their protective application in nuclear reactors. [ABSTRACT FROM AUTHOR]

Background: The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions. Objective: Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk. Methods: A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases. The database search strategy consisted of the narrow search for Standardized MedDRA Query (SMQ) Hypersensitivity, a modified MedDRA query based on SMQ Anaphylactic reaction, and pyrexia-related MedDRA Preferred Terms. The cases identified from the search were further medically reviewed taking into consideration the temporal relationship, seriousness, severity, course, and management of the events, action taken, and outcomes of adverse events. Those cases deemed to have potentially drug-related hypersensitivity were then adjudicated to be confirmed or ruled out. Results: The method was applied to a clinical trial database containing safety data for 421 patients treated with an investigational drug. Application of the methodology led to 19 hypersensitivity cases being identified. Of these, 12 were classified as immediate reactions and 7 as non-immediate reactions. Conclusion: This three-step method provided a thorough and robust way to identify hypersensitivity reactions, including anaphylaxis, in a clinical trial database. This method could be applied to investigational drugs to improve early detection and monitoring of potential safety concerns, subsequent patient safety management strategies, and potentially programme-wide drug development decisions. Algorithmic tools and narrow and/or broad SMQs should be considered when evaluating safety concerns. The authors also recommend a revision of the MedDRA SMQ of Anaphylactic reaction. [ABSTRACT FROM AUTHOR]

Background. Recently, antimicrobial peptides (AMPs) have been investigated for their use in cancer therapy. They have been reported to selectively target and kill cancer cells whilst leaving normal healthy cells unaffected. Certain Anura AMPs have expressed selective cytotoxicity against tumour cells. Aim. To test the potential of Anura AMPs bombinin H2, bombinin H4, temporin A, and temporin L for use as therapeutic agents for non-small cell lung carcinoma (NSCLC). Methods. Cytotoxic effects on NSCLC cell lines A549 and Calu-3 and normal epithelial cell line Beas-2B were tested using the CellTox Green Cytotoxicity Assay. Their haemolytic effects on human erythrocytes were also tested for their clinical relevance. Cell membrane profiling, using MALDI-TOF, was performed to ascertain if membrane characteristics of the NSCLC and Beas-2B cell lines may contribute to the AMPs mode of action. Results. Bombinin H4 (100–1.5 μM, p < 0.05) and temporin A (100–50 μM, p < 0.05) showed selective cytotoxicity towards the NSCLC cell lines. Furthermore, they exhibited low levels of haemolytic activity (bombinin H4, 0.061%; temporin A, 0.874%) comparable to untreated cells. Cell membrane profiling showed the phospholipid composition of normal epithelial cell line Beas-2B to be divergent from the cancerous cell lines. However, there was an overlap in the phospholipid profiles of the NSCLC cell lines supporting the hypothesis that the AMPs may have a selective affinity via the membrane composition of cancerous cell lines. Conclusion. These results suggest that bombinin H4 and temporin A show potential for application in lung cancer therapies. Further in vitro and in vivo studies are required to develop a greater understanding of their use as anticancer agents. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cancer diagnosed in men worldwide; however, few patients are affected by clinically significant disease within their lifetime. Unfortunately, the means to discriminate between patients with indolent disease and those who progress to aggressive prostate cancer is currently unavailable, resulting in over-treatment of patients. We therefore aimed to determine biomarkers of prostate cancer that can be used in the clinic to aid the diagnosis and prognosis. Immunohistochemistry analysis was carried out on prostate cancer specimens with a range of Gleason scores. Samples were stained and analysed for intensity of the Seven Transmembrane Epithelial Antigen of the Prostate (STEAP)-1, -2, -3, -4 and the Divalent Metal Transporter 1 (DMT1) proteins to determine suitable biomarkers for classification of patients likely to develop aggressive prostate cancer. Additionally, these proteins were also analysed to determine whether any would be able to predict future relapse using Kaplan Meier analysis. Data generated demonstrated that the protein expression levels of STEAP2 correlated significantly with Gleason score; furthermore, STEAP4 was a significant predictor of relapse. This data indicates that STEAP2 could be potential prognostic candidate for use in combination with the current prostate cancer detection methods and the presence of STEAP4 could be an indicator of possible relapse. [ABSTRACT FROM AUTHOR]

Controversy exists as to whether African American ( AA) transplant recipients are at risk for developing de novo donor-specific anti-human leucocyte antigen ( HLA) antibody (dn DSA). We studied 341 HLA-mismatched, primary renal allograft recipients who were consecutively transplanted between 3/1999 and 12/2010. Sera were collected sequentially pre- and post-transplant and tested for anti- HLA immunoglobulin G (IgG) via single antigen bead assay. Of the 341 transplant patients (225 AA and 116 non- AA), 107 developed dn DSA at a median of 9.2 months post-transplant. AA patients had a 5-year dn DSA incidence of 35%. This was significantly higher than the 5-year dn DSA incidence for non- AA patients (21%). DQ mismatch (risk) and receiving a living-related donor ( LRD) transplant (protective) were transplant factors associated with dn DSA. Within the AA patient cohort, HLA- DQ mismatch, not-receiving a LRD transplant, nonadherence and BK viraemia were the most common factors associated with early dn DSA (occurring <24 months post-transplant). Nonadherence and pretransplant diabetes history were the strong precursors to late dn DSA. Despite the higher rates of dn DSA in the AA cohort, post-dn DSA survival was the same in AA and non- AA patients. This study suggests that DQ matching, increasing LRD transplantation in AA patients and minimizing under-immunosuppression will be key to preventing dn DSA. [ABSTRACT FROM AUTHOR]

Background The role of anti- HLA- DP antibodies in renal transplantation is poorly defined. This study describes the impact of donor (donor-specific antibody [ DSA]) and non-donor-specific antibodies against HLA- DP antigens in renal transplant patients. Methods Of 195 consecutive patients transplanted between September 2009 and December 2011, 166 primary kidney recipients and their donors were typed (high-resolution) for DP antigens. Sera taken pre-transplant and at 1, 3, 6, 9, and 12 months, and annually post-transplant were retrospectively tested for anti- DP antibodies using single-antigen beads. Results In 81 (49%) patients, anti- DP antibodies were found; 64% (n=52) of patients were positive in the pre-transplant samples and 36% (n=29) were positive exclusively post-transplant. The median time from transplantation to antibody was 20.9 months. Fifty-five percent (n=16) of the de novo anti- DP antibodies were accompanied by another de novo DSA. Anti- DP antibody-positive patients had a higher rate of rejection (compared with anti- DP antibody-negative patients, P=.01). The estimated glomerular filtration rate declined more with anti- DP antibodies (−5.5% vs +26%). Conclusions Antibodies against HLA- DP antigens are common. De novo anti- DP antibodies commonly appear after acute rejection and accompany DSA, which makes it difficult to determine whether anti- DP antibodies are the cause or the consequence of graft injury. [ABSTRACT FROM AUTHOR]

The article focuses on the pathological aspects of colonic perforation. It mentions that colonic perforation is considered as the most common complication of leaving peritoneal dialysis (PD) catheter in place after an immediate posttransplant period. It cites a case study of a 31-year-old man who has developed a colonic perforation after a kidney transplant. It concludes that patient with PD catheters in place is risk to colonic perforation due to an induce peritoneal friability.

Background The Hemodialysis Reliable Outflow (HeRO) vascular access device is a hybrid polytetrafluoroethylene graft-stent construct designed to address central venous occlusive disease. Although initial experience has demonstrated excellent mid-term patency rates, subsequent studies have led to external validity questions. The purpose of this study was to examine a single center experience with this vascular access device in challenging access cases with associated costs. Methods A retrospective study representing the authors' cumulative HeRO vascular access device experience was undertaken. The primary endpoint was graft failure or death, with secondary endpoints including secondary intervention rates and cost. Results Forty-one patients with 15,579 HeRO days and a mean of 12.7 ± 1.5 mo with the vascular access device were available for analysis. Secondary patency was 81.6% at 6 mo and 53.7% at 12 mo. The reintervention rate was 2.84 procedures per HeRO vascular access device year. Associated HeRO costs related to subsequent procedures were estimated at $34,713.63 per patient/y. Conclusions These data on the patency and primary outcome data diverge significantly from initial multicenter studies and represent a real-world application of this technology. It is costly to maintain patency. Use of HeRO vascular access devices should be judicious with outcome expectations reduced. [ABSTRACT FROM AUTHOR]

Summary: Polar bears are uniquely adapted to life in the High Arctic and have undergone drastic physiological changes in response to Arctic climates and a hyperlipid diet of primarily marine mammal prey. We analyzed 89 complete genomes of polar bear and brown bear using population genomic modeling and show that the species diverged only 479–343 thousand years BP. We find that genes on the polar bear lineage have been under stronger positive selection than in brown bears; nine of the top 16 genes under strong positive selection are associated with cardiomyopathy and vascular disease, implying important reorganization of the cardiovascular system. One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans. PaperClip: Display Omitted [ABSTRACT FROM AUTHOR]

Abstract: Prostate cancer is the second most frequently diagnosed cancer worldwide and is the sixth leading cause of cancer deaths in men, yet it varies greatly in its aggressiveness. Currently, it is not possible to adequately differentiate between patients whose tumors will remain indolent and those patients whose disease will progress, resulting in unnecessary aggressive treatment. Consequently, there is an urgent need to identify markers of prostate cancer progression, invasiveness and metastasis to more accurately predict prognosis. The aim of this study was to assess the ability of key epithelial-to-mesenchymal transition molecules in identifying prostate cancer patients who are likely to develop aggressive tumors. Using 215 archival patient tissue samples, immunohistochemistry was applied to examine the expression and sub-cellular localization of E-Cadherin, Snail, Slug, Twist, Vimentin, BMP-2 and BMP-7. Of the seven markers assessed, a significantly increased expression of Snail protein was observed within the nucleus of prostate cancer cells and was strongly associated with increasing Gleason score and clinical stage. In addition, loss of E-Cadherin expression at the cellular membrane of prostate cancer cells was also significantly associated with increasing Gleason score, clinical stage, and additionally, a reduction in survival. [Copyright &y& Elsevier]