Postoperative long­term outcomes of acute normovolemic hemodilution in pancreatic cancer: A propensity score matching analysis.

Acute normovolemic hemodilution (ANH) is a useful intraoperative blood conservation technique. However, the impact on long-term outcomes in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The present study investigated the impact of ANH on long-term outcomes in patients with PDAC undergoing radical surgery. Data from 155 resectable PDAC cases were collected. Patients were categorized according to whether or not they had received intraoperative allogeneic blood transfusion (ABT) or ANH. Postoperative complications, recurrence-free survival (RFS) and disease-specific survival (DSS), before and after propensity score matching (PSM), were compared among patients who did and did not receive ANH. A total of 44 patients (28.4%) were included in the ANH group and 30 patients (19.4%) were included in the ABT group; 81 (52.3%) patients, comprising the standard management (STD) group, received neither ANH nor ABT. The ABT group had the worst prognosis among them. Before PSM, ANH was significantly associated with decreased RFS (P=0.043) and DSS (P=0.029) compared with the STD group before applying Bonferroni correction; however, no significant difference was observed after applying Bonferroni correction. Cox regression analysis identified ANH as an independent prognostic factor for RFS [relative risk (RR), 1.696; P=0.019] and DSS (RR, 1.876; P=0.009). After PSM, the ANH group exhibited less favorable RFS [median survival time (MST), 12.1 vs. 18.1 months; P=0.097] and DSS (MST, 32.1 vs. 50.5 months; P=0.097) compared with the STD group; however, these differences were not statistically significant. In conclusion, while ANH was not as harmful as ABT, it exhibited potentially more negative effects on long-term postoperative outcomes in PDAC than STD.

Endothelial HIFα/PDGF-B to smooth muscle Beclin1 signaling sustains pathological muscularization in pulmonary hypertension.

Mechanisms underlying maintenance of pathological vascular hypermuscularization are poorly delineated. Herein, we investigated retention of smooth muscle cells (SMCs) coating normally unmuscularized distal pulmonary arterioles in pulmonary hypertension (PH) mediated by chronic hypoxia with or without Sugen 5416, and reversal of this pathology. With hypoxia in mice or culture, lung endothelial cells (ECs) upregulated hypoxia-inducible factor 1α (HIF1-α) and HIF2-α, which induce platelet-derived growth factor B (PDGF-B), and these factors were reduced to normoxic levels with re-normoxia. Re-normoxia reversed hypoxia-induced pulmonary vascular remodeling, but with EC HIFα overexpression during re-normoxia, pathological changes persisted. Conversely, after establishment of distal muscularization and PH, EC-specific deletion of Hif1a, Hif2a, or Pdgfb induced reversal. In human idiopathic pulmonary artery hypertension, HIF1-α, HIF2-α, PDGF-B, and autophagy-mediating gene products, including Beclin1, were upregulated in pulmonary artery SMCs and/or lung lysates. Furthermore, in mice, hypoxia-induced EC-derived PDGF-B upregulated Beclin1 in distal arteriole SMCs, and after distal muscularization was established, re-normoxia, EC Pdgfb deletion, or treatment with STI571 (which inhibits PDGF receptors) downregulated SMC Beclin1 and other autophagy products. Finally, SMC-specific Becn1 deletion induced apoptosis, reversing distal muscularization and PH mediated by hypoxia with or without Sugen 5416. Thus, chronic hypoxia induction of the HIFα/PDGF-B axis in ECs is required for non-cell-autonomous Beclin1-mediated survival of pathological distal arteriole SMCs.

Associations between Verbal Fluency and Asymmetry of White Matter Integrity in the Superior Longitudinal Fasciculus in At-Risk Mental States for Psychosis.

Verbal fluency is one of the most severely impaired components of cognitive function in schizophrenia and is also impaired in at-risk mental states (ARMSs) for psychosis. The aim of this study was to explore the markers of disease progression in subjects with ARMSs by comparing the association between the white matter integrity of the superior longitudinal fasciculus (SLF) and verbal fluency in subjects with ARMSs and healthy control (HC) subjects. The correlations of the fractional anisotropy (FA) values on diffusion tensor imaging (DTI) and the laterality index (LI) values of SLF branches I, II, and III with the verbal fluency performance were analyzed in right-handed subjects with ARMSs (ARMS group; n = 18) and HC subjects (HC group; n = 34) aged 18 to 40 years old. In the HC group compared with the ARMS group, the LI values suggested right lateralization of the SLF II and III. Letter fluency was significantly correlated with the LI of the SLF III in both the ARMS and HC groups. The regression coefficient (ß) of this correlation was calculated using the least squares method and yielded a positive number (73.857) in the ARMS group and a negative number (-125.304) in the HC group. The association of the rightward asymmetry of the SLF III with the verbal fluency performance observed in the HC group appeared to be lost in the ARMS group, and this could serve as one of the markers of the pathological progression to psychosis in patients with schizophrenia.

Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study.

PURPOSE: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.

Impact of the combination of abdominal peripheral nerve block and neuromuscular blockade on the surgical space during robot-assisted laparoscopic surgery: a prospective randomized controlled study.

PURPOSE: The impact of the combination of abdominal peripheral nerve block (PNB) and the depth of neuromuscular blockade on the surgical field were assessed. METHODS: Thirty-eight patients undergoing elective robot-assisted laparoscopic radical prostatectomy (RARP) were randomized into two groups: a PNB group (moderate neuromuscular block [train-of-four 1-3 twitches] with abdominal PNB) and a non-PNB group (deep neuromuscular block [post-tetanic count 0-2 twitches] without abdominal PNB). The primary outcome was the change in the depth of the abdominal cavity relaxation assessed by the change in the distance (Δdistance) between the umbilicus port and peritoneum upon pneumoperitoneal pressure increase from 8 to 12 mmHg. The secondary outcomes were the CO2 usage for the pneumoperitoneal pressure increase and the subjective differences in the Surgical Rating Score (SRS) during surgery. RESULTS: The Δdistance and the CO2 usage from 8 to 12 mmHg did not differ significantly between the non-PNB and PNB groups (1.34 ± 0.65 vs. 1.28 ± 0.61 cm, p = 0.763 and 3.64 ± 1.68 vs. 4.34 ± 1.44 L, p = 0.180, respectively). There was also no significant difference in SRS. Comparisons of the Δdistance values for pressure increases from 6 to 8 mmHg, 6 to 10 mmHg and 6 to 12 mmHg between the non-PNB and PNB groups also showed no between-group differences, despite significant intra-group differences (p < 0.001) by pressure increment. CONCLUSIONS: Our findings indicate that moderate neuromuscular block with abdominal PNB maintained an adequate surgical space for RARP, with no significant difference from the space achieved by deep neuromuscular block.

Differences in Psychological Inflexibility Among Men With Erectile Dysfunction Younger and Older Than 40 Years: Web-Based Cross-Sectional Study.

BACKGROUND: Psychological inflexibility is a core concept of acceptance and commitment therapy (ACT), which is a comprehensive, transdiagnostic interpretation of mental health symptoms. Erectile dysfunction (ED) is a condition that affects male sexual performance, involving the inability to achieve and maintain a penile erection sufficient for satisfactory sexual activity. Psychosocial factors primarily influence ED in men younger than 40 years, whereas biological factors are more likely to be the underlying cause in older men. OBJECTIVE: This web-based cross-sectional study examined differences in depression, anxiety, and psychological inflexibility among men with ED younger and older than 40 years in a Japanese population. METHODS: We used a web-based survey to gather data from various community samples. ED was assessed by the International Index of Erectile Function-5 (IIEF-5) questionnaire, while depression, anxiety, and psychological inflexibility were evaluated by the Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 (GAD-7), Acceptance and Action Questionnaire-II (AAQ-II), Cognitive Fusion Questionnaire (CFQ), and Valuing Questionnaire-Obstacle Subscale (VQ-OB) questionnaires. The chi-square test estimated the scores of PHQ-9 and GAD-7 among men with ED, comparing those younger than 40 years and those older than 40 years. Additionally, a two-way ANOVA was conducted with ED severity and age group as independent variables, assessing psychological inflexibility. RESULTS: Valid responses from 643 individuals (mean age 36.19, SD 7.54 years) were obtained. Of these, 422 were younger than 40 years (mean age 31.76, SD 5.00 years), and 221 were older than 40 years (mean age 44.67, SD 2.88 years). There was a statistical difference in the prevalence of depression as judged by PHQ≥10 between men with ED younger and older than 40 years (P<.001). On the other hand, there was no difference in the prevalence of anxiety as judged by GAD≥10 (P=.12). The two-way ANOVA revealed that the interactions for CFQ (P=.04) and VQ-OB (P=.01) were significant. The simple main effect was that men with ED younger than 40 years had significantly higher CFQ (P=.01; d=0.62) and VQ-OB (P<.001; d=0.87) scores compared to those older than 40 years in moderate ED and severe ED. Additionally, it was found that men younger than 40 years with moderate to severe ED had significantly higher CFQ (P=.01; d=0.42) and VQ-OB (P=.02; d=0.38) scores compared to men younger than 40 years without ED. On the other hand, no interaction was found for AAQ-II (P=.16) scores. CONCLUSIONS: To the best of our knowledge, this web-based cross-sectional study is the first to examine the relationship between psychological inflexibility and ED. We conclude that men with moderate and severe ED younger than 40 years have higher psychological inflexibility and might be eligible for ACT.

Fixing the anesthesia research crisis in Japan.

To explore the current status of anesthesia research activity in Japan, we analyzed the number of abstracts presented at the Japanese Society of Anesthesiologists (JSA) annual meetings by several factors including gender, society branches, and subspecialty categories. The number of abstracts at JSA annual meetings has declined sharply since 2016 with no gender gap. A decrease in the neurological field predated the overall decline, but other subspecialty categories showed a similar decline. Although the Tokyo, Tokai-Hokuriku, and Kyushu branches were responsible for more than half of the reduction, the trend was similar among all branches. In a survey regarding academic activities of university hospital residents and faculty, Ph.D. aspirants' rate was only 20-30%. Residents had never presented an abstract at scientific conferences and never published any papers at nearly 40% and 30% of the university hospitals, respectively. Our survey suggests that junior anesthetists are losing interest in research. Senior faculty and mentors must redouble efforts to embed and encourage research in departments and by anesthetists in training. If a revival of anesthesia research in Japan does not occur then a service only specialty awaits.

Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy.

Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, including supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates Notch signaling in aortic SMCs. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of catalytic subunits presenilin (PSEN)-1 or PSEN-2 in elastin aortopathy is not defined. Genetic approaches reveal that endothelial cell-specific Psen1 deletion does not improve elastin aortopathy whereas the deletion of either Psen1 in SMCs or Psen2 globally attenuates Notch pathway and SMC proliferation, mitigating aortic disease. With SMC-specific Psen1 deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. SMC deletion of Psen1 also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Similarly, the pharmacological inhibition of PSEN-1 mitigates SMC accumulation in elastin aortopathy. These findings put forth SMC PSEN-1 as a potential therapeutic target in SVAS.

Crystal structure of the GH-46 subclass III chitosanase from Bacillus circulans MH-K1 in complex with chitotetraose.

BACKGROUND: Chitosanases (EC 3.2.1.132) hydrolyze chitosan which is a polymer of glucosamine (GlcN) linked by ß - 1,4 bonds, and show cleavage specificity against partially acetylated chitosan containing N-acetylglucosamine (GlcNAc) residues. Chitosanases' structural underpinnings for cleavage specificity and the conformational switch from open to closed structures are still a mystery. METHODS: The GH-46 subclass III chitosanase from Bacillus circulans MH-K1 (MH-K1 chitosanase), which also catalyzes the hydrolysis of GlcN-GlcNAc bonds in addition to GlcN-GlcN, has had its chitotetraose [(GlcN)4]-complexed crystal structure solved at 1.35 Å resolution. RESULTS: The MH-K1 chitosanase's (GlcN)4-bound structure has numerous structural similarities to other GH-46 chitosanases in terms of substrate binding and catalytic processes. However, subsite -1, which is absolutely specific for GlcN, seems to characterize the structure of a subclass III chitosanase due to its distinctive length and angle of a flexible loop. According to a comparison of the (GlcN)4-bound and apo-form structures, the particular binding of a GlcN residue at subsite -2 through Asp77 causes the backbone helix to kink, which causes the upper- and lower-domains to approach closely when binding a substrate. CONCLUSIONS: Although GH-46 chitosanases vary in the finer details of the subsites defining cleavage specificity, they share similar structural characteristics in substrate-binding, catalytic processes, and potentially in conformational change. GENERAL SIGNIFICANCE: The precise binding of a GlcN residue to the -2 subsite is essential for the conformational shift that occurs in all GH-46 chitosanases, as shown by the crystal structures of the apo- and substrate-bound forms of MH-K1 chitosanase.

An Acceptance and Commitment Therapy Smartphone Application for Erectile Dysfunction: A Feasibility Study.

Background: Erectile dysfunction (ED) is a multifactorial disorder with both psychogenic and organic components, but psychosocial factors are usually neglected. Objective: The purpose of this study was to develop a smartphone application targeting psychosocial factors of ED and to examine its feasibility, acceptability, and treatment response to determine the parameters for a larger clinical trial. Methods: In this single-arm feasibility study, 8 participants with situational ED were enrolled. Dr. App, a newly developed smartphone treatment application for patients with psychogenic ED consisting of 8 weekly modules based on Acceptance and Commitment Therapy, was delivered. The primary outcome was comparison of the International Index of Erectile Function-15 domain scores measured pre- and post-intervention. Results: Six out of 8 participants completed the Dr. App and the post-intervention measures. The Wilcoxon signed-rank test showed a significant change in erectile function (P < 0.05; r = -0.65) and a significant trend in intercourse satisfaction (P < 0.10; r = -0.47) and overall satisfaction (P < .10; r = -0.47). Additionally, the reliable change index values were used to calculate the number of participants for whom a clinically meaningful difference occurred. The results showed that 33.30% of the participants had clinically meaningful differences in erectile function and 66.70% in intercourse satisfaction and overall satisfaction. On the other hand, no significant differences were shown in orgasmic function and sexual desire. Conclusions: Findings from this study support the feasibility, acceptability, and potential usefulness of the smartphone application targeting psychosocial factors of ED and warrant a larger randomized clinical trial to confirm the results.

Hydrostatic pressure under hypoxia facilitates fabrication of tissue-engineered vascular grafts derived from human vascular smooth muscle cells in vitro.

Biologically compatible vascular grafts are urgently required. The scaffoldless multi-layered vascular wall is considered to offer theoretical advantages, such as facilitating cells to form cell-cell and cell-matrix junctions and natural extracellular matrix networks. Simple methods are desired for fabricating physiological scaffoldless tissue-engineered vascular grafts. Here, we showed that periodic hydrostatic pressurization under hypoxia (HP/HYP) facilitated the fabrication of multi-layered tunica media entirely from human vascular smooth muscle cells. Compared with normoxic atmospheric pressure, HP/HYP increased expression of N-myc downstream-regulated 1 (NDRG1) and the collagen-cross-linking enzyme lysyl oxidase in human umbilical artery smooth muscle cells. HP/HYP increased N-cadherin-mediated cell-cell adhesion via NDRG1, cell-matrix interaction (i.e., clustering of integrin α5ß1 and fibronectin), and collagen fibrils. We then fabricated vascular grafts using HP/HYP during repeated cell seeding and obtained 10-layered smooth muscle grafts with tensile rupture strength of 0.218-0.396 MPa within 5 weeks. Implanted grafts into the rat aorta were endothelialized after 1 week and patent after 5 months, at which time most implanted cells had been replaced by recipient-derived cells. These results suggest that HP/HYP enables fabrication of scaffoldless human vascular mimetics that have a spatial arrangement of cells and matrices, providing potential clinical applications for cardiovascular diseases. STATEMENT OF SIGNIFICANCE: Tissue-engineered vascular grafts (TEVGs) are theoretically more biocompatible than prosthetic materials in terms of mechanical properties and recipient cell-mediated tissue reconstruction. Although some promising results have been shown, TEVG fabrication processes are complex, and the ideal method is still desired. We focused on the environment in which the vessels develop in utero and found that mechanical loading combined with hypoxia facilitated formation of cell-cell and cell-matrix junctions and natural extracellular matrix networks in vitro, which resulted in the fabrication of multi-layered tunica media entirely from human umbilical artery smooth muscle cells. These scaffoldless TEVGs, produced using a simple process, were implantable and have potential clinical applications for cardiovascular diseases.

Association between regional oxygen saturation and central venous saturation in pediatric patients undergoing cardiac surgery: A prospective observational study.

BACKGROUND: We evaluated the correlation between regional oxygen saturation (rSO2 ) in the frontal and right renal dorsum (cerebral rSO2 and somatic rSO2 ) measured by near-infrared spectroscopy (INVOS™ 5100C, Medtronic) and central venous oxygen saturation (ScvO2 ) measured with a fiber-optic oximetry catheter (PediaSat™, Edwards Lifesciences) during surgery in order to determine whether noninvasive rSO2 could be used as an alternative to ScvO2 in pediatric cardiac surgery patients. We evaluated the correlation between regional tissue oxygen saturation (cerebral rSO2 and somatic rSO2 ) measured by near-infrared spectroscopy and other patient measures with central venous oxygen saturation (ScvO2 ) measured with a fiber-optic oximetry catheter to track global oxygen supply demand as a potential alternative or supplement to ScvO2 . PATIENTS AND METHODS: This single-center prospective observational study enrolled 33 children (weight < 10 kg) who underwent cardiac surgery for congenital heart disease between February 2018 and November 2021. ScvO2 , cerebral rSO2 , and somatic rSO2 were recorded simultaneously after anesthesia induction and central venous catheter placement. Pearson's correlation coefficient and Bland-Altman analysis were used to determine the relationship between ScvO2 and rSO2 . We conducted correlation, Bland Altman, and multiple regression analyses to identify associations between rSO2 , patient measures, and ScvO2 values. RESULTS: The patients' median age was 11.0 (quartile 2.0-16.0) months. Their weight was 7.2 (quartile 4.5-9.2) kg. Cerebral rSO2 was significantly positively correlated with ScvO2 (r2 = 0.29, p = .002 in all patients; r2 = 0.61, p = .013 in the patients without mixing at the atrial level), whereas somatic rSO2 was not. The Bland-Altman analysis demonstrated biases [95% confidence interval; 95% CI] (lower and upper limits of agreement [95% CI]) of 0.27% [-4.26 to 4.80] (-24.79 [-32.61 to -16.96] to 25.33 [17.50 to 33.16]) between cerebral rSO2 and ScvO2 and 0.91% [-5.48 to 7.30] (-34.43 [-45.47 to -23.39] to 36.25 [25.21 to 47.29]) between somatic rSO2 and ScvO2 . Preoperative brain natriuretic peptide (BNP) and SpO2 were independent variables associated with ScvO2 and cerebral and somatic rSO2 . CONCLUSION: Cerebral rSO2 , SpO2 , and BNP were significantly correlated with ScvO2 , although the cerebral rSO2 correlation was greater for lesions without atrial mixing. rSO2 , BNP, and SpO2 might be used to track changes in ScvO2 but cerebral rSO2 is not sufficiently precise to replace it.

Experience with transesophageal echocardiography for mitral valve plasty in the remote stage after esophagectomy with gastric tube reconstruction via the retrosternal route.

A 69-year-old male patient with mitral valve prolapse was scheduled for mitral valve plasty. Sixteen years earlier, he had undergone right open thoracotomy for esophageal cancer with subtotal esophagectomy, cervicothoraco-abdominal three-region dissection, posterior mediastinal tube reconstruction, and cervical anastomosis. Postoperatively, the patient had a treatment- and recurrence-free course, and an upper gastrointestinal endoscopy performed 2 years prior revealed no abnormality. We scheduled a transesophageal echocardiography for mitral valve surgery. We attempted to insert the probe but felt resistance at the height of the mid-thoracic region, and the image quality was poor, so we abandoned the intraoperative diagnosis. The surgery was performed as planned, and when the probe was manipulated again at the time of cardiopulmonary withdrawal, the mitral valve could be observed. The mitral valve was judged to be sufficiently repaired, and the surgery was terminated. There were no complications associated with transesophageal echocardiography.

Solitary fibrous tumor of the breast: A case report.

INTRODUCTION: Solitary fibrous tumors (SFTs) are uncommon mesenchymal neoplasms that comprise <2 % of all soft tissue tumors. They are a diagnostically challenging group of neoplasms that can occur essentially anywhere. Molecular or genetic testing of soft tissue tumors will increasingly add to the foundation of distinctive histologic features, as accurate diagnosis is critical for appropriate treatment. CASE PRESENTATION: A 28-year-old woman was referred to our hospital for a left breast mass. Ultrasonography showed an oval hypoechoic mass with partially obscured boundaries. Surgical specimens revealed spindle tumor cells surrounding the mammary ducts and were immunoreactive for both CD34 and STAT6, suggesting SFTs. However, the infiltration of spindle tumor cells into the surrounding fat, and the storiform-like pattern made us consider dermatofibrosarcoma protuberans (DFSP) as a differential diagnosis. Lack of amplification of the COL1A1-PDGFB fusion gene, a characteristic feature of DFSP, led to our definitive diagnosis of breast SFT. DISCUSSION: The presence of STAT6 in tumor cell nuclei is a highly sensitive immunohistochemical marker for SFT. In our case, morphological features evoked the differential diagnosis of DFSP and we investigated the COL1A1-PDGFB fusion gene. The diagnostic process of reliably performing careful morphological examination and immunohistochemical marker test, and then obtain conviction by molecular cytogenetic technique is more and more important for soft tissue tumors. CONCLUSIONS: We report a quite uncommon case of breast SFT and excluded DFSP as a differential diagnosis. If it is difficult to distinguish between these diseases, molecular cytogenetic analysis would be required for accurate diagnosis.

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A2A Receptor Antagonist/Inverse Agonist.

KW-6356 is a novel adenosine A2A (A2A) receptor antagonist/inverse agonist, and its efficacy as monotherapy in Parkinson's disease (PD) patients has been reported. Istradefylline is a first-generation A2A receptor antagonist approved for use as adjunct treatment to levodopa/decarboxylase inhibitor in adult PD patients experiencing "OFF" episodes. In this study, we investigated the in vitro pharmacological profile of KW-6356 as an A2A receptor antagonist/inverse agonist and the mode of antagonism and compared them with istradefylline. In addition, we determined cocrystal structures of A2A receptor in complex with KW-6356 and istradefylline to explore the structural basis of the antagonistic properties of KW-6356. Pharmacological studies have shown that KW-6356 is a potent and selective ligand for the A2A receptor (the -log of inhibition constant = 9.93 ± 0.01 for human receptor) with a very low dissociation rate from the receptor (the dissociation kinetic rate constant = 0.016 ± 0.006 minute-1 for human receptor). In particular, in vitro functional studies indicated that KW-6356 exhibits insurmountable antagonism and inverse agonism, whereas istradefylline exhibits surmountable antagonism. Crystallography of KW-6356- and istradefylline-bound A2A receptor have indicated that interactions with His2506.52 and Trp2466.48 are essential for the inverse agonism, whereas the interactions at both deep inside the orthosteric pocket and the pocket lid stabilizing the extracellular loop conformation may contribute to the insurmountable antagonism of KW-6356. These profiles may reflect important differences in vivo and help predict better clinical performance. SIGNIFICANCE STATEMENT: KW-6356 is a potent and selective adenosine A2A receptor antagonist/inverse agonist and exhibits insurmountable antagonism, whereas istradefylline, a first-generation adenosine A2A receptor antagonist, exhibits surmountable antagonism. Structural studies of adenosine A2A receptor in complex with KW-6356 and istradefylline explain the characteristic differences in the pharmacological properties of KW-6356 and istradefylline.

The Perioperative Frontal Relative Ratio of the Alpha Power of Electroencephalography for Predicting Postoperative Delirium After Highly Invasive Surgery: A Prospective Observational Study.

BACKGROUND: We investigated the associations between postoperative delirium (POD) and both the relative ratio of the alpha (α)-power of electroencephalography (EEG) and inflammatory markers in a prospective, single-center observational study. METHODS: We enrolled 84 patients who underwent radical cancer surgeries with reconstruction for esophageal cancer, oral floor cancer, or pharyngeal cancer under total intravenous anesthesia. We collected the perioperative EEG data and the perioperative data of the inflammatory markers, including neutrophil gelatinase-associated lipocalin, presepsin, procalcitonin, C-reactive protein, and the neutrophil-lymphocyte ratio (NLR). The existence of POD was evaluated based on the Intensive Care Delirium Screening Checklist. We compared the time-dependent changes in the relative ratio of the EEG α-power and inflammatory markers between the patients with and without POD. RESULTS: Four of the 84 patients were excluded from the analysis. Of the remaining 80 patients, 25 developed POD and the other 55 did not. The relative ratio of the α-power at baseline was significantly lower in the POD group than the non-POD group (0.18 ± 0.08 vs 0.28 ± 0.11, P < .001). A time-dependent decline in the relative ratio of α-power in the EEG during surgery was observed in both groups. There were significant differences between the POD and non-POD groups in the baseline, 3-h, 6-h, and 9-h values of the relative ratio of α-power. The preoperative NLR of the POD group was significantly higher than that of the non-POD group (2.88 ± 1.04 vs 2.22 ± 1.00, P < .001), but other intraoperative inflammatory markers were comparable between the groups. Two multivariable logistic regression models demonstrated that the relative ratio of the α-power at baseline was significantly associated with POD. CONCLUSIONS: Intraoperative frontal relative ratios of the α-power of EEG were associated with POD in patients who underwent radical cancer surgery. Intraoperative EEG monitoring could be a simple and more useful tool for predicting the development of postoperative delirium than measuring perioperative acute inflammatory markers. A lower relative ratio of α-power might be an effective marker for vulnerability of brain and ultimately for the development of POD.

Molecular mechanisms regulating extracellular matrix-mediated remodeling in the ductus arteriosus.

Progressive remodeling throughout the fetal and postnatal period is essential for anatomical closure of the ductus arteriosus (DA). Internal elastic lamina interruption and subendothelial region widening, elastic fiber formation impairment in the tunica media, and intimal thickening are distinctive features of the fetal DA. After birth, the DA undergoes further extracellular matrix-mediated remodeling. Based on the knowledge obtained from mouse models and human disease, recent studies revealed a molecular mechanism of DA remodeling. In this review, we focus on matrix remodeling and regulation of cell migration/proliferation associated with DA anatomical closure and discuss the role of prostaglandin E receptor 4 (EP4) signaling and jagged1-Notch signaling as well as myocardin, vimentin, and secretory components including tissue plasminogen activator, versican, lysyl oxidase, and bone morphogenetic proteins 9 and 10.

"Anti-cancer" effect of ketamine in comparison with MK801 on neuroglioma and lung cancer cells.

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, is commonly used to induce anaesthesia during cancer surgery and relieve neuropathic and cancer pain. This study was conducted to assess whether ketamine has any inhibiting effects on neuroglioma (H4) and lung cancer cells (A549) in vitro. The cultured H4 and A549 cells were treated with ketamine and MK801 (0.1, 1, 10, 100, or 1000 µM) for 24 h. The expressions of glutamate receptors on both types of cancer cells were assessed with qRT-PCR. In addition, cell proliferation and migration were assessed with cell counting Kit-8 and wound healing assays. Cyclin D1, matrix metalloproteinase 9 (MMP9), phosphorylation of extracellular signal-regulated kinase (pERK), and cleaved-caspase-3 expression together with reactive oxygen species (ROS) were also assessed with Western blot, immunostaining, and/or flowcytometry. NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors were expressed on both H4 and A549 cells. Ketamine inhibited cancer cell proliferation and migration in a dose-dependent manner by suppressing the cell cycle and inducing apoptosis. Ketamine decreased cyclin D1, pERK, and MMP9 expression. In addition, ketamine increased ROS and cleaved caspase-3 expression and induced apoptosis. The anti-cancer effect of ketamine was more pronounced in A549 cells when compared with H4 cells. MK801 showed similar effects to those of ketamine. Ketamine suppressed cell proliferation and migration in both neuroglioma and lung cancer cells, likely through the antagonization of NMDA receptors.