71 research outputs found
Influence of Comorbidities on Therapeutic Progression of Diabetes Treatment in Australian Veterans: A Cohort Study
BACKGROUND: This study assessed whether the number of comorbid conditions unrelated to diabetes was associated with a delay in therapeutic progression of diabetes treatment in Australian veterans. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort study was undertaken using data from the Australian Department of Veterans' Affairs (DVA) claims database between July 2000 and June 2008. The study included new users of metformin or sulfonylurea medicines. The outcome was the time to addition or switch to another antidiabetic treatment. The total number of comorbid conditions unrelated to diabetes was identified using the pharmaceutical-based comorbidity index, Rx-Risk-V. Competing risk regression analyses were conducted, with adjustments for a number of covariates that included age, gender, residential status, use of endocrinology service, number of hospitalisation episodes and adherence to diabetes medicines. Overall, 20134 veterans were included in the study. At one year, 23.5% of patients with diabetes had a second medicine added or had switched to another medicine, with 41.4% progressing by 4 years. The number of unrelated comorbidities was significantly associated with the time to addition of an antidiabetic medicine or switch to insulin (subhazard ratio [SHR] 0.87 [95% CI 0.84–0.91], P<0.001). Depression, cancer, chronic obstructive pulmonary disease, dementia, and Parkinson's disease were individually associated with a decreased likelihood of therapeutic progression. Age, residential status, number of hospitalisations and adherence to anti-diabetic medicines delayed therapeutic progression. CONCLUSIONS / SIGNIFICANCE: Increasing numbers of unrelated conditions decreased the likelihood of therapeutic progression in veterans with diabetes. These results have implications for the development of quality measures, clinical guidelines and the construction of models of care for management of diabetes in elderly people with comorbidities.Agnes I. Vitry, Elizabeth E. Roughead, Adrian K. Preiss, Philip Ryan, Emmae N. Ramsay, Andrew L. Gilbert, Gillian E. Caughey, Sepehr Shakib, Adrian Esterman, Ying Zhang and Robyn A. McDermot
siRNA Off-Target Effects Can Be Reduced at Concentrations That Match Their Individual Potency
Small interfering RNAs (siRNAs) are routinely used to reduce mRNA levels for a specific gene with the goal of studying its function. Several studies have demonstrated that siRNAs are not always specific and can have many off-target effects. The 3′ UTRs of off-target mRNAs are often enriched in sequences that are complementary to the seed-region of the siRNA. We demonstrate that siRNA off-targets can be significantly reduced when cells are treated with a dose of siRNA that is relatively low (e.g. 1 nM), but sufficient to effectively silence the intended target. The reduction in off-targets was demonstrated for both modified and unmodified siRNAs that targeted either STAT3 or hexokinase II. Low concentrations reduced silencing of transcripts with complementarity to the seed region of the siRNA. Similarly, off-targets that were not complementary to the siRNA were reduced at lower doses, including up-regulated genes that are involved in immune response. Importantly, the unintended induction of caspase activity following treatment with a siRNA that targeted hexokinase II was also shown to be a concentration-dependent off-target effect. We conclude that off-targets and their related phenotypic effects can be reduced for certain siRNA that potently silence their intended target at low concentrations
Crystal Structure Analysis Reveals Functional Flexibility in the Selenocysteine-Specific tRNA from Mouse
Selenocysteine tRNAs (tRNA(Sec)) exhibit a number of unique identity elements that are recognized specifically by proteins of the selenocysteine biosynthetic pathways and decoding machineries. Presently, these identity elements and the mechanisms by which they are interpreted by tRNA(Sec)-interacting factors are incompletely understood.We applied rational mutagenesis to obtain well diffracting crystals of murine tRNA(Sec). tRNA(Sec) lacking the single-stranded 3'-acceptor end ((ΔGCCA)RNA(Sec)) yielded a crystal structure at 2.0 Å resolution. The global structure of (ΔGCCA)RNA(Sec) resembles the structure of human tRNA(Sec) determined at 3.1 Å resolution. Structural comparisons revealed flexible regions in tRNA(Sec) used for induced fit binding to selenophosphate synthetase. Water molecules located in the present structure were involved in the stabilization of two alternative conformations of the anticodon stem-loop. Modeling of a 2'-O-methylated ribose at position U34 of the anticodon loop as found in a sub-population of tRNA(Sec)in vivo showed how this modification favors an anticodon loop conformation that is functional during decoding on the ribosome. Soaking of crystals in Mn(2+)-containing buffer revealed eight potential divalent metal ion binding sites but the located metal ions did not significantly stabilize specific structural features of tRNA(Sec).We provide the most highly resolved structure of a tRNA(Sec) molecule to date and assessed the influence of water molecules and metal ions on the molecule's conformation and dynamics. Our results suggest how conformational changes of tRNA(Sec) support its interaction with proteins
Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis
Molecular events leading to epithelial ovarian cancer are poorly understood but
ovulatory hormones and a high number of life-time ovulations with concomitant
proliferation, apoptosis, and inflammation, increases risk. We identified genes
that are regulated during the estrous cycle in murine ovarian surface epithelium
and analysed these profiles to identify genes dysregulated in human ovarian
cancer, using publically available datasets. We identified 338 genes that are
regulated in murine ovarian surface epithelium during the estrous cycle and
dysregulated in ovarian cancer. Six of seven candidates selected for
immunohistochemical validation were expressed in serous ovarian cancer,
inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium.
Most were overexpressed in ovarian cancer compared with ovarian surface
epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2
were expressed as highly in fallopian tube epithelium as in ovarian cancer. We
prioritised the 338 genes for those likely to be important for ovarian cancer
development by in silico analyses of copy number aberration and
mutation using publically available datasets and identified genes with
established roles in ovarian cancer as well as novel genes for which we have
evidence for involvement in ovarian cancer. Chromosome segregation emerged as an
important process in which genes from our list of 338 were over-represented
including two (BUB1, NCAPD2) for which there
is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface
epithelium in proestrus and predicted to have a driver mutation in ovarian
cancer, was examined in a larger cohort of serous ovarian cancer where patients
with lower NUAK2 expression had shorter overall survival. In conclusion,
defining genes that are activated in normal epithelium in the course of
ovulation that are also dysregulated in cancer has identified a number of
pathways and novel candidate genes that may contribute to the development of
ovarian cancer
An examination of the self-referent executive processing model of test anxiety: control, emotional regulation, self-handicapping, and examination performance
According to the self-referent executive processing (S-REF) model, test anxiety develops from interactions between three systems: executive self-regulation processes, self-beliefs, and maladaptive situational interactions. Studies have tended to examine one system at a time, often in conjunction with how test anxiety relates to achievement outcomes. The aim of this study was to enable a more thorough test of the S-REF model by examining one key construct from each of these systems simultaneously. These were control (a self-belief construct), emotional regulation through suppression and reappraisal (an executive process), and self-handicapping (a maladaptive situational interaction). Relations were examined from control, emotional regulation, and self-handicapping to cognitive test anxiety (worry), and subsequent examination performance on a high-stakes test. Data were collected from 273 participants in their final year of secondary education. A structural equation model showed that higher control was indirectly related to better examination performance through lower worry, higher reappraisal was indirectly related to worse examination performance through higher worry, and higher self-handicapping was related to worse examination performance through lower control and higher worry. These findings suggest that increasing control and reducing self-handicapping would be key foci for test anxiety interventions to incorporate. © 2018 The Author(s
Expectancy of success, subjective task-value, and message frame in the appraisal of value-promoting messages made prior to a high-stakes examination
© 2016 Springer Science+Business Media Dordrecht Previous research has examined how subjective task-value and expectancy of success influence the appraisal of value-promoting messages used by teachers prior to high-stakes examinations. The aim of this study was to examine whether message-frame (gain or loss-framed messages) also influences the appraisal of value-promoting messages. Two hundred and fifty-two participants in Years 12 and 13 read vignettes of fictional students who were high or low in subjective-task value, and expectancy of success, and asked to imagine how that student would appraise either a gain or loss-framed message. A challenge appraisal followed vignettes with high subjective task-value and high expectancy of success whereas a threat appraisal followed vignettes with high subjective task-value and low expectancy of success. A loss-framed message resulted in a stronger threat appraisal, and a gain-framed message in a greater disregarding appraisal for the vignette with high subjective task-value and high expectancy of success. Value-promoting messages can be appraised in different ways depending on combinations of intrapersonal (subjective task-value and expectancy of success) and interpersonal (message-frame) influences. © 2016 Springer Science+Business Media Dordrech
Molecular cloning and expression of the gene encoding ADP-glucose pyrophosphorylase from the cyanobacteriumAnabaena sp. strain PCC 7120
Comparing Pioglitazone to Insulin with Respect to Cancer, Cardiovascular and Bone Fracture Endpoints, Using Propensity Score Weights
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