Purpose
Dexmedetomidine is frequently used as a sedative agent for orthopedic surgery patients undergoing total hip or knee arthroplasty. Although the benefits of dexmedetomidine are well described ...in the literature, there is also potential for harm, especially regarding the hemodynamic effects of dexmedetomidine in the postoperative setting.
Methods
This historical cohort study included all primary unilateral total hip or knee arthroplasties conducted from April 2017 to February 2020 in a single, university-affiliated, tertiary care centre (Jewish General Hospital, Montreal, QC, Canada). We used multivariable logistic regression to analyze the predictors for postoperative hypotension, defined as a systolic blood pressure < 90 mm Hg or any systolic blood pressure while on a vasopressor infusion in the postanesthesia care unit. Models were validated using calibration and discrimination with bootstrapping technique.
Results
One thousand five hundred and eighty-eight patients were included in this study. Postoperative hypotension occurred in 413 (26%) patients. Statistically significant predictors for postoperative hypotension included female sex (adjusted odds ratio aOR, 3.24; 95% confidence interval CI, 2.29 to 4.58), a history of transient ischemic attack or cerebrovascular accident (aOR, 1.97; 95% CI, 1.04 to 3.72), and intraoperative dexmedetomidine use (aOR, 2.61; 95% CI, 1.99 to 3.42). Moreover, the risk of postoperative hypotension was approximately two times higher than baseline, with a total intraoperative dexmedetomidine dose above 50 μg (relative risk, 1.99; 95% CI, 1.63 to 2.44;
P
< 0.001). A higher preoperative systolic blood pressure (aOR, 0.98; 95% CI, 0.97 to 0.99) was a protective factor for postoperative hypotension.
Conclusion
In this historical cohort study, dexmedetomidine was a strong risk factor for postoperative hypotension in total hip or knee arthroplasty patients. Dexmedetomidine, and particularly at high cumulative doses above 50 μg, should be administered judiciously in high-risk surgical patients to minimize the risk of postoperative hypotension.
Objectives. Acute pain trajectories are associated with long-term outcomes such as persistent pain and functional disability in adults. However, there are limited data on acute postoperative pain ...trajectories in the pediatric population. The aims of this study were to investigate acute postoperative pain trajectories, their predictors, and their impact on long- term outcomes in adolescents with idiopathic scoliosis. Methods. We evaluated the preoperative pain intensity, use of analgesics, psychosocial measures and physical functioning of adolescents scheduled to undergo spinal fusion, and their average 6-hour self-reported pain intensity scores for their entire hospital stay. Six months after surgery, baseline variables were reassessed. We used growth mixture modeling to conduct acute postoperative pain trajectory analysis and to identify predictors of pain trajectories. Generalized linear models were conducted to determine whether acute pain trajectories predict long-term outcomes. Results. One hundred and six patients were included in the best-fitted acute pain trajectory model that included four classes that differed in initial pain intensity and rates of change over time. Preoperative pain catastrophizer status and use of analgesics significantly predicted pain trajectory membership. Furthermore, at the 6-month follow-up, patients experiencing moderate-to-severe pain in the acute postoperative period were more likely to report higher levels of pain severity, use pain medication, and miss a greater number of school/work days due to back pain in the last three months. Discussion. Preoperative assessment and analyzing the progression of pain in the acute postoperative period can help identify those at risk of negative long-term outcomes after surgery.
Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 ...in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the
gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wild-type (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (
) and area under the plasma concentration-time curve (AUC
) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced
by 80% and 88%, respectively, while the AUC
values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine
and AUC
values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT: A novel mouse model with targeted disruption of the
gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the
KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.
Stable intronic sequence RNAs (sisRNAs) have been found in Xenopus tropicalis, human cell lines, and Epstein-Barr virus; however, the biological significance of sisRNAs remains poorly understood. We ...identify sisRNAs in Drosophila melanogaster by deep sequencing, reverse transcription polymerase chain reaction, and Northern blotting. We characterize a sisRNA (sisR-1) from the regena (rga) locus and show that it can be processed from the precursor messenger RNA (pre-mRNA). We also document a cis-natural antisense transcript (ASTR) from the rga locus, which is highly expressed in early embryos. During embryogenesis, ASTR promotes robust rga pre-mRNA expression. Interestingly, sisR-1 represses ASTR, with consequential effects on rga pre-mRNA expression. Our results suggest a model in which sisR-1 modulates its host gene expression by repressing ASTR during embryogenesis. We propose that sisR-1 belongs to a class of sisRNAs with probable regulatory activities in Drosophila.
Maternally inherited noncoding RNAs (ncRNAs) can regulate zygotic gene expression across generations 1–4. Recently, many stable intronic sequence RNAs (sisRNAs), which are byproducts of pre-mRNA ...splicing, were found to be maternally deposited and persist till zygotic transcription in Xenopus and Drosophila 5–7. In various organisms, sisRNAs can be in linear or circular conformations, and they have been suggested to regulate host gene expression 5–10. It is unknown whether maternally deposited sisRNAs can regulate zygotic gene expression in the embryos. Here, we show that a maternally inherited sisRNA (sisR-4) from the deadpan locus is important for embryonic development in Drosophila. Mothers, but not fathers, mutant for sisR-4 produce embryos that fail to hatch. During embryogenesis, sisR-4 promotes transcription of its host gene (deadpan), which is essential for development. Interestingly, sisR-4 functions by activating an enhancer present in the intron where sisR-4 is encoded. We propose that a maternal sisRNA triggers expression of its host gene via a positive feedback loop during embryogenesis.
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•Deadpan intron encodes a sisRNA sisR-4•Maternally inherited sisR-4 is required for development•sisR-4 promotes transcription of its host gene deadpan
Stable intronic sequence RNAs are maternally deposited in frogs and fruit flies, suggesting that they may regulate gene expression. Tay and Pek show that the deadpan intron encodes a maternally inherited intronic RNA that promotes embryonic development by enhancing host gene transcription in fruit flies.
Increasing evidence has revealed the importance of cancer stem cells (CSCs) in carcinogenesis. Although liver CSCs have been identified in hepatocellular carcinoma (HCC) cell lines, no data have ...shown the presence of these cells in human settings. The present study was designed to delineate CSCs serially from HCC cell lines, human liver cancer specimens to blood samples, using CD90 as a potential marker. The number of CD90+ cells increased with the tumorigenicity of HCC cell lines. CD45−CD90+ cells were detected in all the tumor specimens, but not in the normal, cirrhotic, and parallel nontumorous livers. In addition, CD45−CD90+ cells were detectable in 90% of blood samples from liver cancer patients, but none in normal subjects or patients with cirrhosis. A significant positive correlation between the number of CD45−CD90+ cells in the tumor tissues and the number of CD45−CD90+ cells in the blood samples was identified. CD90+ cells sorted from cell lines and CD45−CD90+ cells from the tumor tissues and blood samples of liver cancer patients generated tumor nodules in immunodeficient mice. Serial transplantation of CD90+ cells from tumor xenografts generated tumor nodules in a second and subsequently third batch of immunodeficient mice. Treatment of CD90+ CSCs with anti‐human CD44 antibody induced cell apoptosis in a dose‐dependent manner. Conclusion: Identification of CD45−CD90+ CSCs in both tumor tissues and circulation suggests that CD45−CD90+ could be used as a marker for human liver cancer and as a target for the diagnosis and therapy of this malignancy. (HEPATOLOGY 2008.)
Gene expression involves the transcription and splicing of nascent transcripts through the removal of introns. In Drosophila, a double-stranded RNA binding protein Disco-interacting protein 1 (DIP1) ...targets INE-1 stable intronic sequence RNAs (sisRNAs) for degradation after splicing. How nascent transcripts that also contain INE-1 sequences escape degradation remains unknown. Here we observe that these nascent transcripts can also be bound by DIP1 but the Drosophila homolog of SON (Dsn) protects them from unproductive degradation in ovaries. Dsn localizes to the satellite body where active decay of INE-1 sisRNAs by DIP1 occurs. Dsn is a repressor of DIP1 posttranslational modifications (primarily sumoylation) that are assumed to be required for efficient DIP1 activity. Moreover, the pre-mRNA destabilization caused by Dsn depletion is rescued in DIP1 or Sumo heterozygous mutants, suggesting that Dsn is a negative regulator of DIP1. Our results reveal that under normal circumstances nascent transcripts are susceptible to DIP1-mediated degradation, however intronic sequences are protected by Dsn until intron excision has taken place.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Indicators have emerged as a powerful communication tool for complex phenomena in the shift towards quantitative measurement. Indigenous peoples have not been immune to the representation and ...monitoring of their lives using indicators. Across many of these standard metrics, they consistently underperform. As a result, resources globally and nationally are often targeted at improving these metrics of indigenous populations. Indigenous peoples have not been silent on this matter. In challenging these universal frameworks, they mobilised a self-determination movement which is centred on their worldviews and priorities. The endorsement and ratification of the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP) have further created a space and impetus to ask how the UNDRIP can be implemented to support indigenous groups around the world to drive their own development agenda. Using a framework informed by UNDRIP and Indigenous knowledge this paper has two aims: 1) to explore if and how the SDGs have reframed policy relating to Indigenous peoples in Australia and Aotearoa New Zealand and 2) to explore how indigenous communities are developing their own indicators to inform their development needs and in the process mitigate the negative governance effects of national goal and target setting.
Upon splicing, introns are rapidly degraded. Hence, RNAs derived from introns are commonly deemed as junk sequences. However, the discoveries of intronic-derived small nucleolar RNAs (snoRNAs), small ...Cajal body associated RNAs (scaRNAs) and microRNAs (miRNAs) suggested otherwise. These non-coding RNAs are shown to play various roles in gene regulation. In this review, we highlight another class of intron-derived RNAs known as stable intronic sequence RNAs (sisRNAs). sisRNAs have been observed since the 1980 s; however, we are only beginning to understand their biological significance. Recent studies have shown or suggested that sisRNAs regulate their own host’s gene expression, function as molecular sinks or sponges, and regulate protein translation. We propose that sisRNAs function as an additional layer of gene regulation in the cells.
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