Purpose
The effects of remimazolam on autonomic nervous activity have not been elucidated. We investigated the differential effects of remimazolam and propofol on autonomic nervous activity during ...anesthesia induction.
Methods
Thirty patients were randomly divided into a remimazolam group or a propofol group for anesthesia induction. Hemodynamics and indices of heart rate variability were recorded before and after anesthesia. Low frequency power (LF; 0.04–0.15 Hz, ms
2
) and high frequency power (HF; 0.15–0.4 Hz, ms
2
) were calculated from power spectral density of heart rate variability. LF reflects both sympathetic and parasympathetic activities and HF reflects parasympathetic activity. To investigate the balance between sympathetic and parasympathetic activities, the normalized unit (%) of LF (LF nu) and that of HF (HF nu) were calculated. Changes in LF nu (ΔLF nu) before and after anesthesia (ΔLF nu = LF nu at awake—LF nu after anesthesia) were compared between the groups.
Results
Remimazolam and propofol decreased blood pressure and power spectral density of heart rate variability. Remimazolam did not change LF nu and HF nu, while propofol increased LF nu and decreased HF nu (
P
= 0.020). ΔLF nu in the remimazolam group (1.4 ± 23.6%) were less than that in the propofol group (19.3 ± 22.4%,
P
= 0.0415).
Conclusion
Remimazolam and propofol decreased autonomic nervous activity during anesthesia induction. Remimazolam preserved the balance of sympathetic and parasympathetic activities, while propofol modulated it to sympathetic dominance.
Remote ischemic preconditioning (RIPC) offers cardioprotection against myocardial ischemia–reperfusion injury. The humoral factors involved in RIPC that are released from parasympathetically ...innervated organs have not been identified. Previous studies showed that ghrelin, a hormone released from the stomach, is associated with cardioprotection. However, it is unknown whether or not ghrelin is involved in the mechanism of RIPC. This study aimed to determine whether ghrelin serves as one of the humoral factors in RIPC. RIPC group rats were subjected to three cycles of ischemia and reperfusion for 5 min in two limbs before left anterior descending (LAD) coronary artery ligation. Unacylated ghrelin (UAG) group rats were given 0.5 mcg/kg UAG intravenously 30 min before LAD ligation. Plasma levels of UAG in all groups were measured before and after RIPC procedures and UAG administration. Additionally, JAK2/STAT3 pathway inhibitor (AG490) was injected in RIPC and UAG groups to investigate abolishment of the cardioprotection of RIPC and UAG. Plasma levels of UAG, infarct size and phosphorylation of STAT3 were compared in all groups. Infarct size was significantly reduced in RIPC and UAG groups, compared to the other groups. Plasma levels of UAG in RIPC and UAG groups were significantly increased after RIPC and UAG administration, respectively. The cardioprotective effects of RIPC and UAG were accompanied by an increase in phosphorylation of STAT3 and abolished by AG490. This study indicated that RIPC reduces myocardial ischemia and reperfusion injury through UAG-induced activation of JAK/STAT pathway. UAG may be one of the humoral factors involved in the cardioprotective effects of RIPC.
BACKGROUND:Dexmedetomidine (DEX) has a direct cardioprotective effect against ischemia/reperfusion injury through endothelial nitric oxide synthase (eNOS) phosphorylation via α2-adrenoreceptor ...(α2-AR). By using spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat models, the cardioprotective effect of DEX in hypertrophied myocardium and the differential characteristics of cardiac α2-AR and the I1 imidazoline receptor (I1R) were examined.
METHODS:Langendorff-perfused rat hearts underwent 40 minutes of global ischemia followed by 120 minutes of reperfusion in the presence or absence of DEX before ischemia. Infarct size was measured, and eNOS phosphorylation was assessed by Western blotting. The presence and expression of the receptors were assessed by immunohistochemistry, real-time reverse transcriptase polymerase chain reaction, and Western blotting.
RESULTS:In WKY, DEX significantly decreased infarct size and increased phosphorylated-eNOS/eNOS. These effects were counteracted by yohimbine (α2-AR antagonist) and efaroxan (α2-AR and I1R antagonist). In SHR, DEX significantly decreased infarct size, and the effect was counteracted by efaroxan but not yohimbine. DEX did not alter phosphorylated-eNOS/eNOS in SHR. α2-AR and I1R were observed in WKY and SHR hearts. Although alpha2A-AR and alpha2B-AR messenger RNA and protein levels were upregulated in SHR, I1R expression was comparable between the 2 species.
CONCLUSIONS:In the hypertrophied heart, DEX maintains its direct cardioprotective effect against ischemia/reperfusion injury via I1R in an eNOS-nondependent manner despite upregulation of α2-AR.
Telescopic crowns made from zirconia/alumina can be manufactured using computer-aided design/computer-aided manufacturing systems. For their successful clinical use, a suitable retentive force must ...be maintained over an extended period. However, it is unclear how retentive force and secondary crown settling change after repeated crown insertion and removal. The aim of the present study was to investigate the changes in retentive force and secondary crown settling of telescopic crowns made from zirconia/alumina. Primary crowns with tapers of 2° and 4° were used. Repeated insertion and removal tests were performed for 10,000 cycles at a cyclic load of 50 N. The loads applied when measuring retentive force and settling were 50 and 100 N. The number of insertions and removals had a significant effect on retentive force and settling at both loads (p<0.01). Taper also had a significant effect on retentive force and settling at both loads (p<0.01).
Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by
...and CRISPR/Cas9 analyses, is a critical determinant of
expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes
were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer. SIGNIFICANCE: RNA splicing factor SF3B2 is essential for the generation of an androgen receptor (AR) variant that renders prostate cancer cells resistant to AR-targeting therapy.
http://cancerres.aacrjournals.org/content/canres/79/20/5204/F1.large.jpg.
Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5-expressing stem/progenitor cells are ...essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5-expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5
cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5
epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5
stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5
stem/progenitor cells to uterine disorders.
The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the ...utility of the DAPT score in the Japanese population.
In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto Coronary Revascularization Demonstrating Outcome Study in Kyoto Registry Cohort-2, RESET Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial, and NEXT NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score <2 (low DS).
Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%,
=0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%,
=0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%,
=0.03; 1.5% versus 0.8%,
=0.002; 0.7% versus 0.3%,
<0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%,
<0.001; 1.0% versus 1.6%,
=0.03, respectively).
In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.
Dexmedetomidine (DEX), a highly selective alpha2-adrenoceptors agonist, is not only a sedative drug used during mechanical ventilation in the intensive care unit but also a cardio-protective drug ...against ischemia–reperfusion injury (IRI). Numerous preclinical in vivo and ex vivo studies, mostly evaluating the effect of DEX pretreatment in healthy rodents, have shown the efficacy of DEX in protecting the hearts from IRI. However, whether DEX can maintain its cardio-protective effect in hearts with comorbidities such as diabetes has not been fully elucidated. Multiple clinical trials have reported promising results, showing that pretreatment with DEX can attenuate cardiac damage in patients undergoing cardiac surgery. However, evidence of the post-treatment effects of DEX in clinical practice remains limited. In this narrative review, we summarize the previously reported evidence of DEX-induced cardio-protection against IRI and clarify the condition of the hearts and the timing of DEX administration that has not been tested. With further investigations evaluating these knowledge gaps, the use of DEX as a cardio-protective drug could be further facilitated in the management of patients undergoing cardiac surgery and might be considered in a broader area of clinical settings beyond cardiac surgery, including patients with acute myocardial infarction.
Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, directly protects hearts against ischemia/reperfusion (I/R) injury. However, the detailed mechanism has not been fully ...elucidated. We studied differentially expressed mRNAs and miRNAs after DEX administration in rat hearts by comprehensive analysis. Additionally, bioinformatics analysis was applied to explore candidate genes and pathways that might play important roles in DEX-induced cardioprotection. The results of microarray analysis showed that 165 mRNAs and 6 miRNAs were differentially expressed after DEX administration. Through bioinformatics analysis using differentially expressed mRNAs, gene ontology (GO) terms including MAP kinase tyrosine/serine/threonine phosphatase activity and pathways including the p53 pathway were significantly enriched in the down-regulated mRNAs.
and
were associated with the GO term of MAP kinase tyrosine/serine/threonine phosphatase activity and the p53 pathway, respectively. On the other hand, no significant pathway was found in the target mRNAs of deregulated miRNAs. The results indicated some possible key genes and pathways that seem to be of significance in DEX-induced cardioprotection, although miRNAs seem to be unlikely to contribute to cardioprotection induced by DEX.
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