AimsInnate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. The interleukin-1 receptor (IL-1R)-mediated, MyD88-dependent nuclear factor kappa B (NF-κB) activation pathway plays an important role in the induction of innate immunity and inflammation. However, the role of the IL-1R-MyD88 pathway in myocardial I/R injury has not been thoroughly investigated. We hypothesized that inhibition of the interaction of IL-1R with MyD88 will attenuate myocardial ischaemic injury through reducing inflammatory responses.Methods and resultsMale C57BL/6 mice were subjected to myocardial ischaemia (45 min) followed by reperfusion (4 h). In the treatment group, after mice were subjected to ischaemia (45 min), the TIR/BB-loop mimetic (AS-1), which inhibits the interaction of IL-1R with MyD88, was administered immediately before reperfusion. Hearts were harvested and cellular proteins were isolated for immunoprecipitation and immunoblotting. AS-1 administration significantly decreased infarct size by 32.92 compared with the untreated I/R group. Ejection fraction and fractional shortening in AS-1-treated mice were also significantly increased by 18.0 and 25.6, respectively, compared with the untreated I/R group. AS-1 administration significantly decreased the I/R-increased interaction between IL-1R and MyD88, attenuated the I/R-increased NF-κB binding activity, and reduced levels of inflammatory cytokines and adhesion molecules in the myocardium compared with the untreated I/R group. In addition, AS-1 administration significantly decreased myocardial myeloperoxidase activity by 23.6 and neutrophil infiltration in the myocardium compared with the untreated I/R group.ConclusionThe results demonstrated an important role for the IL-1R-mediated MyD88-dependent signalling pathway in myocardial I/R injury. The data suggest that modulation of the IL-1R/MyD88 interaction could be a strategy for reducing myocardial ischaemic injury.

We examined internal consistency and test-retest reliability of a measure of dispositional optimism, the Life Orientation Test-Revised, in 121 opiate-dependent patients seeking methadone treatment. Internal consistency was adequate at baseline (α=.69) and follow-up (α=.72). Low socioeconomic status and being on disability were significantly associated with reduced internal consistency; ethnic and educational differences approached significance. Test-retest reliability was good (ICC=.72), varying across gender, race, ethnicity, education, employment and income (ICC Range=.24-.85). Criterion validity was strong; the LOT-R was significantly negatively correlated with hopelessness (r=-.65, p<.001) and depression (r=-.60, p<.001). Findings support the use of this measure of optimism and pessimism to assess positive cognitive and emotional attributes and improve treatment strategies for opiate-dependent individuals. Future research should address the measurement and significance of optimism in minority, low socioeconomic status and poorly-educated individuals.

Respiratory syncytial virus (RSV) is the leading cause of respiratory illness in children worldwide. RSV has a negative sense RNA genome, which is the template for viral mRNA transcription and genome replication, and encodes a polymerase to carry out viral RNA synthesis. The promoters for RSV transcription and genome replication are found in a 44-nucleotide (nt), 3´-extragenic region called the leader (Le). Replication is initiated opposite the first nt of the Le, and transcription of the first gene begins at position +45, at a gene start (GS) sequence. However, transcription is also dependent on sequence within Le1-12. Interestingly, Le nucleotides 3-12 bear strong similarity to a GS signal. We hypothesized that this GS-like sequence is the recruitment site for transcribing polymerase. To test this hypothesis, we examined RNA synthesis events at the Le promoter. We identified a previously undescribed RNA initiation site at Le position +3 (Le+3) that was used frequently during RSV infection. Initiation at Le+3 led to the production of a small ~25 nt RNA. Le+3 initiation was shown to occur independently of replication initiation at +1, indicating it is a bona fide initiation site. Mutation of Le1-12 to increase similarity to a GS resulted in elongation of Le+3 RNA and a decrease in transcription initiation at the GS, demonstrating that the Le initiation sequence alters polymerase processivity and impacts downstream transcription events. Preliminary experiments to determine the function of the small RNA showed that it increased levels of viral RNA replication, suggesting it may be involved in influencing a switch from transcription to replication. These studies suggest a model for RSV transcription initiation, whereby the transcribing polymerase enters at the 3´&ndash;end of the genome, initiates RNA synthesis from Le+3 and generates a small RNA, and is then positioned to initiate transcription at the first GS. The small RNA that is generated may act as a feedback molecule to promote RNA replication. These findings provide a greater understanding of polymerase behavior at the promoter and may inform rational drug and vaccine design.

Background: Correctional nurses make up a large part of the corrections workforce and have increasing responsibility for making decisions about patient care in the opioid dependent incarcerated patients. The National Commission on Correctional Health Care (NCCHC) has intoxication and withdrawal standards that advocate individuals entering a correctional facility under the influence or undergoing withdrawal from opioids have their therapy continued, or a plan for appropriate referral for treatment. The NCCHC standard that incarcerated opioid dependent inmates have their therapy continued or a plan for appropriate referral for treatment is not adhered to consistently, as the current process lacks organization. Purpose: The purpose of this quality improvement project was to develop an adult opioid dependence referral for treatment tool for opioid use dependent patients to be utilized by correctional nurses and providers working in the corrections intake medical facility with posttest evaluation. Theoretical Framework: Peplau’s nurse-patient relationship theory was used. Methods: A descriptive, exploratory design was utilized. Results: A majority of the nurses acknowledged the usefulness of the Nursing Opioid Referral for Treatment Algorithm (NORTA) in facilitating the adult opioid dependence referral process. In addition, of the 20 nurses surveyed, 18 nurses agreed that the NORTA tool was relevant to the adult opioid dependence referral process. Most claimed that the NORTA facilitated the opioid dependence referral process. Conclusion: The pain management algorithm is an effective referral method for opioid users as it contributes to patient safety through safe prescription and careful assessment of patient risk regarding opioid use. The findings from this project may impact nursing practice by identification of a new organized approach to enhance the current opioid dependence referral process.

Indiana University-Purdue University Indianapolis (IUPUI) / Thiamin diphosphate (ThDP)-dependent enzymes catalyze a wide range of reactions including the oxidative and nonoxidative decarboxylation of 2-keto acids, carboligation reactions, the cleavage of C-C bonds, and the formation of C-S, C-N, and C-O bonds. Surprisingly, given this diversity, all ThDP-dependent enzyme catalyzed reactions proceed through essentially the same intermediate. This suggests that these enzymes share a common ancestry and have evolved to become the diverse group of enzymes seen today. Sequence alignments have revealed that all ThDP-dependent enzymes share two common ThDP binding domains, the PYR domain and the PP domain. In addition to these conserved domains, over time, other domains have been added creating further diversity in this superfamily. For instance, the TH3 domain, found in many ThDP-dependent enzymes, serves the function of binding additional cofactors such as FAD in enzymes like acetohydroxyacid synthase (AHAS) but in others, like pyruvate decarboxylase (PDC), it has lost this function completely. The work presented here focuses on ThDP-dependent decarboxylases. In this thesis, several evolutionary aspects of this group of enzymes will be examined including (i) the characterization of an evolutionary forerunner in the presence of a mechanism-based inhibitor, (ii) the characterization of the minor isozymes of pyruvate decarboxylase from Saccharomyces cerevisiae, and (iii) the development of a selection method to increase the efficiency of the site-saturation mutagenesis used to study ThDP-dependent enzyme evolution.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20943号 / 理博第4395号 / 新制||理||1631(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 三木 邦夫, 教授 杉山 弘, 教授 秋山 芳展 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

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