The immunomodulatory effect of ketamine in colorectal cancer surgery: a randomized-controlled trial.

PURPOSE: Ketamine's inhibitory action on the N-methyl-D-aspartate receptor and anti-inflammatory effects may provide beneficial immunomodulation in cancer surgery. We investigated the effect of subanesthetic-dose ketamine as an adjunct to desflurane anesthesia on natural killer (NK) cell activity and inflammation in patients undergoing colorectal cancer surgery. METHODS: A total of 100 patients were randomly assigned to a control or ketamine group. The ketamine group received a bolus of 0.25 mg·kg-1 ketamine five minutes before the start of surgery, followed by an infusion 0.05 mg·kg-1·hr-1 until the end of surgery; the control group received a similar amount of normal saline. We measured NK cell activity and proinflammatory cytokines (interleukin-6 [IL-6] and tumour necrosis factor-α [TNF-α]) before surgery and one, 24, and 48 hr after surgery. C-reactive protein (CRP) was measured before surgery and one, three, and five days after surgery. Carcinoembryonic antigen and cancer recurrence/metastasis were assessed two years after surgery. RESULTS: The NK cell activity was significantly decreased after surgery in both groups, but the change was not different between groups in the linear mixed model analysis (P = 0.47). Changes in IL-6, TNF-α, CRP, and carcinoembryonic antigen levels were not different between groups (P = 0.27, 0.69, 0.99, and 0.97, respectively). Cancer recurrence within 2 years after surgery was similar between groups (10% vs 8%, P = 0.62). CONCLUSIONS: Intraoperative low-dose ketamine administration did not convey any favourable impacts on overall postoperative NK cell activity, inflammatory responses, and prognosis in colorectal cancer surgery patients. TRIAL REGISTRATION: www.clinicaltrial.gov (NCT03273231); registered 6 September 2017.

RéSUMé: OBJECTIF: L'action inhibitrice de la kétamine sur le récepteur du N-méthyle-D-aspartate et ses effets anti-inflammatoires pourraient procurer une immunomodulation bénéfique lors d'une chirurgie oncologique. Nous avons étudié l'effet de la kétamine en dose sous-anesthésique en complément à une anesthésie au desflurane sur l'activité des cellules tueuses naturelles (NK) et l'inflammation chez les patients subissant une chirurgie de cancer colorectal. MéTHODE: Au total, 100 patients ont été randomisés à un groupe témoin ou kétamine. Le groupe kétamine a reçu un bolus de 0,25 mg·kg−1 de kétamine cinq minutes avant le début de la chirurgie, suivi d'une perfusion de 0,05 mg·kg−1·h−1 jusqu'à la fin de la chirurgie; le groupe témoin a reçu une quantité similaire de solution physiologique salée. Nous avons mesuré l'activité des cellules NK et des cytokines pro-inflammatoires (interleukine-6 [IL-6] et facteur de nécrose tumorale α [TNF-α]) avant la chirurgie et une, 24 et 48 heures après la chirurgie. La protéine C réactive (CRP) a été mesurée avant la chirurgie puis un, trois et cinq jours après la chirurgie. L'antigène carcinoembryonnaire et la récurrence du cancer ou les métastases ont été évalués deux ans après la chirurgie. RéSULTATS: L'activité des cellules NK a été significativement réduite après la chirurgie dans les deux groupes, mais le changement ne différait pas entre les groupes dans l'analyse de modèle mixte linéaire (P = 0,47). Les changements dans les taux d'IL-6, de TNF-α, de CRP, et d'antigène carcinoembryonnaire n'étaient pas différents entre les groupes (P = 0,27, 0,69, 0,99 et 0,97, respectivement). La récidive du cancer au cours des deux années suivant la chirurgie était similaire entre les groupes (10 % vs 8 %, P = 0,62). CONCLUSION: L'administration peropératoire de kétamine de faible dose ne s'est pas traduite par un quelconque impact favorable sur l'activité postopératoire g des cellules NK, la réaction inflammatoire, et le pronostic chez les patients de chirurgie de cancer colorectal. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT03273231); enregistrée le 6 septembre 2017.

Effect of perioperative sodium bicarbonate administration on renal function following cardiac surgery for infective endocarditis: a randomized, placebo-controlled trial.

BACKGROUND: Patients with infective endocarditis (IE) have an elevated risk of renal dysfunction because of extensive systemic inflammation and use of nephrotoxic antibiotics. In this randomized, placebo-controlled trial, we investigated whether perioperative sodium bicarbonate administration could attenuate postoperative renal dysfunction in patients with IE undergoing cardiac surgery. METHODS: Seventy patients randomly received sodium chloride (n = 35) or sodium bicarbonate (n = 35). Sodium bicarbonate was administered as a 0.5 mmol/kg loading dose for 1 h commencing with anesthetic induction, followed by a 0.15 mmol/kg/h infusion for 23 h. The primary outcome was peak serum creatinine (SCr) level during the first 48 h postoperatively. The incidence of acute kidney injury, SCr level, estimated glomerular filtration rate, and major morbidity endpoints were assessed postoperatively. RESULTS: The peak SCr during the first 48 h postoperatively (bicarbonate vs. CONTROL: 1.01 (0.74, 1.37) mg/dl vs. 0.88 (0.76, 1.27) mg/dl, P = 0.474) and the incidence of acute kidney injury (bicarbonate vs. CONTROL: 29% vs. 23%, P = 0.584) were similar in both groups. The postoperative increase in SCr above baseline was greater in the bicarbonate group than in the control group on postoperative day 2 (0.21 (0.07, 0.33) mg/dl vs. 0.06 (0.00, 0.23) mg/dl, P = 0.028) and postoperative day 5 (0.23 (0.08, 0.36) mg/dl vs. 0.06 (0.00, 0.23) mg/dl, P = 0.017). CONCLUSIONS: Perioperative sodium bicarbonate administration had no favorable impact on postoperative renal function and outcomes in patients with IE undergoing cardiac surgery. Instead, it was associated with possibly harmful renal effects, illustrated by a greater increase in SCr postoperatively, compared to control. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01920126 . Registered on 31 July 2013.

Comparison of the effects of patient-controlled epidural and intravenous analgesia on postoperative bowel function after laparoscopic gastrectomy: a prospective randomized study.

BACKGROUND: Although laparoscopic surgery significantly reduces surgical trauma compared to open surgery, postoperative ileus is a frequent and significant complication after abdominal surgery. Unlike laparoscopic colorectal surgery, the effects of epidural analgesia on postoperative recovery after laparoscopic gastrectomy are not well established. We compared the effects of epidural analgesia to those of conventional intravenous (IV) analgesia on the recovery of bowel function after laparoscopic gastrectomy. METHOD: Eighty-six patients undergoing laparoscopic gastrectomy randomly received either patient-controlled epidural analgesia with ropivacaine and fentanyl (Epi PCA group) or patient-controlled IV analgesia with fentanyl (IV PCA group), beginning immediately before incision and continuing for 48 h thereafter. The primary endpoint was recovery of bowel function, evaluated by the time to first flatus. The balance of the autonomic nervous system, pain scores, duration of postoperative hospital stay, and complications were assessed. RESULTS: The time to first flatus was shorter in the epidural PCA group compared with the IV PCA group (61.3 ± 11.1 vs. 70.0 ± 12.3 h, P = 0.001). Low-frequency/high-frequency power ratios during surgery were significantly higher in the IV PCA group, compared with baseline and those in the epidural PCA group. The epidural PCA group had lower pain scores during the first 1 h postoperatively and required less analgesics during the first 6 h postoperatively. CONCLUSIONS: Compared with IV PCA, epidural PCA facilitated postoperative recovery of bowel function after laparoscopic gastrectomy without increasing the length of hospital stay or PCA-related complications. This beneficial effect of epidural analgesia might be attributed to attenuation of sympathetic hyperactivation, improved analgesia, and reduced opioid use.

The Effects of Perioperative Anesthesia and Analgesia on Immune Function in Patients Undergoing Breast Cancer Resection: A Prospective Randomized Study.

Introduction: Perioperative anesthesia and analgesia exacerbate immunosuppression in immunocompromised cancer patients. The natural killer (NK) cell is a critical part of anti-tumor immunity. We compared the effects of two different anesthesia and analgesia methods on the NK cell cytotoxicity (NKCC) in patients undergoing breast cancer surgery. Methods: Fifty patients undergoing breast cancer resection were randomly assigned to receive propofol-remifentanil anesthesia with postoperative ketorolac analgesia (Propofol-ketorolac groups) or sevoflurane-remifentanil anesthesia with postoperative fentanyl analgesia (Sevoflurane-fentanyl group). The primary outcome was NKCC, which was measured before and 24 h after surgery. Post-surgical pain scores and inflammatory responses measured by white blood cell, neutrophil, and lymphocyte counts were assessed. Cancer recurrence or metastasis was evaluated with ultrasound and whole body bone scan every 6 months for 2 years after surgery. Results: The baseline NKCC (%) was comparable between the two groups (P = 0.082). Compared with the baseline value, NKCC (%) increased in the Propofol-ketorolac group [15.2 (3.2) to 20.1 (3.5), P = 0.048], whereas it decreased in the Sevoflurane-fentanyl group [19.5 (2.8) to 16.4 (1.9), P = 0.032]. The change of NKCC over time was significantly different between the groups (P = 0.048). Pain scores during 48 h after surgery and post-surgical inflammatory responses were comparable between the groups. One patient in the Sevoflurane-fentanyl group had recurrence in the contralateral breast and no metastasis was found in either group. Conclusions: Propofol anesthesia with postoperative ketorolac analgesia demonstrated a favorable impact on immune function by preserving NKCC compared with sevoflurane anesthesia and postoperative fentanyl analgesia in patients undergoing breast cancer surgery.

Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery.

Acute kidney injury (AKI) following cardiac surgery is closely interrelated with hemodynamic instability and sympathetic activity, and adversely influences prognosis. Here, we investigated in a randomized placebo-controlled trial whether dexmedetomidine, an α2 adrenoreceptor agonist, could prevent AKI after valvular heart surgery. Two hundred patients undergoing valvular heart surgery were randomly assigned to equal placebo or treatment groups. Dexmedetomidine was infused at a rate of 0.4 µg/kg/h starting immediately after anesthetic induction and continuing for 24 h after surgery. We then assessed the incidence of AKI during the first 48 postoperative hours, hemodynamic variables, and a composite of major morbidity end points. The incidence of AKI, based on Acute Kidney Injury Network criteria, was significantly lower in the treatment group compared with the control group (14 vs. 33%). The dexmedetomidine group exhibited a significantly lower incidence of a composite of major morbidity end points (21 vs. 38%) and a significantly shorter length of intensive care unit stay (3 [2, 3] days vs. 3 [2, 4] days) compared with the control group. Thus, perioperative infusion of dexmedetomidine effectively reduced both the incidence and severity of AKI, and improved outcome in patients undergoing valvular heart surgery without untoward hemodynamic side effects.

Effects of Dexmedetomidine on Changes in Heart Rate Variability and Hemodynamics During Tracheal Intubation.

Sympathetic hyperactivation during tracheal intubation prolongs the QT interval and increases the risk of arrhythmias. We investigated if dexmedetomidine pretreatment affected autonomic nervous system balance and QT intervals during intubation. Sixty-six patients were randomized to receive 1.0 µg/kg fentanyl (group F, n = 22), 0.5 µg/kg dexmedetomidine (group D0.5, n = 22), or 1.0 µg/kg dexmedetomidine (group D1.0, n = 22) before induction. Autonomic nervous system balance was assessed by the ratio of low-frequency/high-frequency (LF/HF) power for heart rate variability at baseline (T0), before intubation (T1), and after intubation (T2). QT intervals were corrected by the Bazett's formula (QTc) and compared at baseline, before intubation, and 1, 2, and 3 minutes after intubation. The LF/HF ratio was higher after intubation compared with that at T0 in group F (P < 0.001). There were no significant changes in groups D0.5 and D1.0. The LF/HF ratio was significantly higher in group F compared with those in groups D0.5 and D1.0 after intubation (7.9 vs. 2.1 and 2.5; P < 0.001). The heart rate was increased for 3 minutes after intubation in group F, whereas only for 1 minute after intubation in groups D0.5 and D1.0, compared with that at baseline. More patients in group F had QTc greater than 440 ms compared with that in group D0.5 or D1.0 (8 vs. 1 and 2; P = 0.005) at 1 minute after intubation. In contrast to 1.0 µg/kg fentanyl, pretreatment with 0.5 or 1.0 µg/kg dexmedetomidine suppressed sympathetic hyperactivity and attenuated QTc prolongation during intubation.

Comparison of three sedation regimens for drug-induced sleep endoscopy.

PURPOSE: Drug-induced sleep endoscopy (DISE) allows for direct airway observation in patients with obstructive sleep apnea. This study compared the safety profiles and efficacies of three regimens for DISE. METHODS: Sixty-six patients were randomly assigned to receive propofol alone (n = 22), a propofol-remifentanil combination (n = 22), or a dexmedetomidine-remifentanil combination (n = 22). Remifentanil was infused at a concentration of 1.5 ng·ml(-1) in the propofol-remifentanil and dexmedetomidine-remifentanil groups, whereas saline was infused in the propofol group. The propofol and propofol-remifentanil groups received propofol at a starting concentration of 1.0 µg·ml(-1), then 0.1 µg·ml(-1) increments at 5 min intervals. The dexmedetomidine-remifentanil group received 1.0 µg·kg(-1) loading dose of dexmedetomidine for 10 min and then 0.2 µg·kg(-1)·h(-1) increments at 5 min intervals. RESULTS: The incidence of oxygen desaturation was significantly higher in the propofol-remifentanil group compared with that of the dexmedetomidine-remifentanil group (77 vs. 45%, respectively, P = 0.024). Even with a maximum dose of dexmedetomidine (1.4 µg·kg(-1)·h(-1)), 50% of the dexmedetomidine-remifentanil group did not reach sufficient sedation and required additional propofol. Cough reflex occurred in five patients of propofol group and in neither of the other groups (P = 0.004). CONCLUSIONS: The propofol-remifentanil combination was associated with a higher incidence of desaturation. The dexmedetomidine-remifentanil combination was associated with inadequate sedation in one half of the patients, even though it produced less respiratory depression. Addition of remifentanil reduced the cough reflex.

The effects of arginase inhibitor on lung oxidative stress and inflammation caused by pneumoperitoneum in rats.

BACKGROUND: Pneumoperitoneum-induced oxidative stress and organ injury are known to be associated with nitric oxide (NO) inactivation. Because arginase competes with NO synthase (NOS) for a common substrate, L-arginine, arginase inhibition may increase NO bioavailability. Therefore, we evaluated the ability of the arginase inhibitor, 2 (S)-amino-6-boronohexanoic acid (ABH), to attenuate pneumoperitoneum-induced decrease of NO bioavailability and lung injury. METHODS: Thirty rats were randomly divided into the following groups: 1) the PP-ABH group received a subcutaneous injection of ABH (5 mg/kg) 1 h before induction of pneumoperitoneum (insufflation to intraperitoneal pressure of 15 mmHg for 60 min); 2) the PP group received saline by subcutaneous injection 1 h before induction of pneumoperitoneum; and 3) the control group received saline by subcutaneous injection before a sham procedure with no gas insufflation. After desufflation, blood was collected to determine levels of plasma nitrite, NOS, inflammatory cytokines, and malondialdehyde, a marker of oxidative stress. Lung tissue was obtained for histological evaluation. RESULTS: We found that plasma nitrite levels were lower in the PP group and higher in the PP-ABH group, compared with controls (P <0.01 and P <0.05, respectively). In the PP group, endothelial NOS activity was decreased and inducible NOS activity was increased compared with the PP-ABH and control groups. Malondialdehyde levels increased 3-fold in the PP group and 2-fold in the PP-ABH group compared with controls. Tumor necrosis factor-α, interleukin-6, and interleukin-1ß levels were elevated in the PP group compared to the control group, but the increase in cytokine production was attenuated or blocked in the PP-ABH group. Lung injury scores were 4.8-fold higher in the PP group and 2-fold higher in the PP-ABH group compared with controls (P <0.001 and P <0.01, respectively). DISCUSSION: Pneumoperitoneum decreases NO bioavailability and increases the inflammation cytokines, resulting in organ injuries. Inhibition of arginase activity could maintain NO bioavailability by attenuating pneumoperitoneum-induced changes in NOS activity. In addition, arginase inhibition attenuated the oxidative stress and inflammation and decreased the severity of lung injury caused by pneumoperitoneum. CONCLUSIONS: By increasing NO bioavailability and suppressing oxidative stress and inflammation, pretreatment with an arginase inhibitor may protect against lung injury caused by pneumoperitoneum.

Incidence and outcome of contrast-associated acute kidney injury assessed with Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria in critically ill patients of medical and surgical intensive care units: a retrospective study.

BACKGROUND: Contrast medium used for radiologic tests can decrease renal function. However there have been few studies on contrast-associated acute kidney injury in intensive care unit (ICU) patients. The objective of this study was to evaluate the incidence, characteristics, and outcome of contrast-associated acute kidney injury (CA-AKI) patients using the Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria in critically ill patients in the ICU. METHODS: We conducted a retrospective study of adult patients who underwent contrast-enhanced radiologic tests from January 2011 to December 2012 in a 30-bed medical ICU and a 24-bed surgical ICU. RESULTS: The study included 335 patients, and the incidence of CA-AKI was 15.5%. The serum creatinine and estimated glomerular filtration rate values in the CA-AKI patients did not recover even at discharge from the hospital compared with the values prior to the contrast use. Among 52 CA-AKI patients, 55.8% (n = 29) had pre-existing kidney injury and 44.2% (n = 23) did not. The CA-AKI patients were divided into risk (31%), injury (31%), and failure (38%) by the RIFLE classification. The percentage of patients in whom AKI progressed to a more severe form (failure, loss, end-stage kidney disease) increased from 38% to 45% during the hospital stay, and the recovery rate of AKI was 17% at the time of hospital discharge. Because the Acute Physiology and Chronic Health Evaluation (APACHE) II score was the only significant variable inducing CA-AKI, higher APACHE II scores were associated with a higher risk of CA-AKI. The ICU and hospital mortality of patients with CA-AKI was significantly higher than in patients without CA-AKI. CONCLUSIONS: CA-AKI is associated with increases in hospital mortality, and can be predicted by the APACHE score. TRIAL REGISTRATION: NCT01807195 on March. 06. 2013.

Improved sedation with dexmedetomidine-remifentanil compared with midazolam-remifentanil during catheter ablation of atrial fibrillation: a randomized, controlled trial.

AIMS: Anaesthesia is required for catheter ablation of atrial fibrillation (A-fib) to achieve patient comfort and immobilization to avoid map shifts. This study compared the analgesic and sedative efficacies of dexmedetomidine-remifentanil with those of midazolam-remifentanil for catheter ablation of A-fib. METHODS AND RESULTS: Ninety patients were randomized to receive either intermittent midazolam boluses (1-2 mg) with 3.6-7.2 µg/kg/h of remifentanil (MR group) or dexmedetomidine 0.2-0.7 µg/kg/h after a loading dose of 1 µg/kg with 1.2-2.4 µg/kg/h of remifentanil (DR group). The sedation level assessed by the Ramsay sedation and bispectral index scores, haemodynamic variables, pain score (10-point numerical scale), and satisfaction levels of the patients and cardiologists (5-point numerical scale) were recorded. The Ramsay sedation score was significantly higher, and the bispectral index score was lower in the DR group (P< 0.001) compared with the MR group starting 10 min after drug administration. The incidence of desaturation (SpO2 < 90%) was significantly greater in the MR group compared with the DR group (15 vs. 1, P < 0.001). The pain score was significantly lower (1.72 ± 1.65 vs. 0.95 ± 1.10, P = 0.021), and the satisfaction levels of interventionists were significantly higher (2.50 ± 0.71 vs. 3.00 ± 0.63, P = 0.001) in the DR group compared with the MR group. CONCLUSION: The combination of dexmedetomidine and remifentanil provided deeper sedation, less respiratory depression, better analgesia, and higher satisfaction for the interventionist during catheter ablation of A-fib compared with midazolam plus remifentanil, even at a lower dose of remifentanil.

Risk stratification model integrating nutritional and inflammatory factors for predicting 1-year mortality after valvular heart surgery: a retrospective cohort study.

INTRODUCTION: Existing risk-scoring systems for cardiac surgery include only standard preoperative factors without considering nutritional and inflammatory status or intraoperative factors. The objective of this study was to develop a comprehensive prediction model for mortality incorporating nutritional, inflammatory, and perioperative factors in patients undergoing valvular heart surgery. MATERIALS AND METHODS: In this retrospective review of 2046 patients who underwent valvular heart surgery, Cox and LASSO regression analyses were performed to identify independent prognostic factors for 1-year postoperative mortality among various perioperative factors known to affect prognosis, including objective nutritional and inflammatory indices. A novel nomogram model incorporating selected prognostic factors was developed, and its discrimination ability was evaluated using the C-index. The model was validated in internal and external cohorts. RESULTS: The 1-year mortality rate after valvular heart surgery was 5.1% (105 of 2046 patients) and was significantly associated with several preoperative objective inflammatory and nutritional indices. Cox and LASSO analyses identified the following five independent prognostic factors for mortality: monocyte-to-lymphocyte ratio (an objective inflammatory index), EuroSCORE II, Controlling Nutritional Status score, cardiopulmonary bypass time, and number of erythrocyte units transfused intraoperatively. The nomogram model incorporating these five factors had a C-index of 0.834 (95% CI: 0.791-0.877), which was higher than that of EuroSCORE II alone (0.744, 95% CI: 0.697-0.791) ( P <0.001). The nomogram achieved good discrimination ability, with C-indices of 0.836 (95% CI: 0.790-0.878) and 0.727 (95% CI: 0.651-0.803) in the internal and external validation cohorts, respectively, and showed well-fitted calibration curves. CONCLUSIONS: A nomogram model incorporating five inflammatory, nutritional, and perioperative factors, as well as EuroSCORE II, was a better predictor of 1-year mortality after valvular heart surgery than EuroSCORE II alone, with good discrimination and calibration power for predicting mortality in both internal and external validation cohorts.

Association of serum creatinine trajectories with one-year mortality after valvular heart surgery: a retrospective cohort study.

BACKGROUND: Acute renal dysfunction is defined by the maximum increase in serum creatinine (sCr) without considering the pattern of change in sCr. We aimed to identify longitudinal patterns (trajectories) of postoperative sCr concentrations and investigate their association with long-term outcomes in patients undergoing valvular heart surgery. MATERIALS AND METHODS: In this retrospective review of 3,436 patients who underwent valvular heart surgery, we applied trajectory projection cluster analysis to identify the trajectories of sCr changes from baseline during the seven postoperative days. Primary and secondary endpoints were to investigate the associations of sCr trajectories with mortality using Kaplan-Meier curves and Cox proportional hazards regression analysis, and a composite of major adverse kidney events (MAKEs) at one year after surgery, respectively. RESULTS: Four clusters were identified: Clusters 1 and 2, a minimal change in sCr (90.1% of patients); Cluster 3, a significant and persistent increase in sCr (4.1% of patients); and Cluster 4, a significant but transient increase in sCr (5.8% of patients). The one-year postoperative mortality rate was higher in Cluster 3 (18.4%) and Cluster 4 (11.6%) than in Cluster 1+2 (2.7%). The Kaplan-Meier survival curve demonstrated significant differences in mortality rates among the clusters (log-rank test, P<0.001). In the multivariable Cox analysis, the sCr trajectory cluster was an independent prognostic factor for mortality. Cluster 3 had a higher prevalence of MAKEs (37.6%) compared with Cluster 1+2 (6.8%, P<0.001) and Cluster 4 (24.1%, P=0.045). The cluster was an independent prognostic factor for MAKEs. CONCLUSION: The sCr trajectory clusters exhibited significantly different risks of mortality and MAKEs at one year after surgery. Through these sCr trajectories, we confirmed that both the extent of sCr increase and its sustainability during the first seven postoperative days were closely associated with the long-term prognosis after valvular heart surgery.

Association of Pre- and Post-Donation Renal Function with Midterm Estimated Glomerular Filtration Rate in Living Kidney Donors: A Retrospective Study.

PURPOSE: The estimated glomerular filtration rate (eGFR) at 6 months after donation (eGFR6m) is strongly associated with the risk of end-stage renal disease in living kidney donors. This study aimed to investigate the incidence of eGFR6m <60 mL/min/1.73 m² (eGFR6m <60) and identify the risk factors that can predict the occurrence of eGFR6m <60 in living kidney donors. MATERIALS AND METHODS: Living kidney donors who underwent nephrectomy at Severance Hospital between January 2009 and December 2019 were identified. We excluded 94 of 1233 donors whose creatinine values at 6 months after donation were missing. The risk factors for eGFR6m <60 were assessed using multivariate regression analysis. The optimal cutoff points for candidate risk factors for predicting eGFR6m <60 occurrence were determined using the Youden index. RESULTS: The eGFR6m <60 occurred in 17.3% of the participants. Older age (≥44 years), history of hypertension, lower preoperative eGFR (<101 mL/min/1.73 m²), and degree of increase in creatinine levels on postoperative day 2 compared to those before surgery (ΔCr2_pre) (≥0.39 mg/dL) increased the risk of eGFR6m <60. The addition of ΔCr2_pre to preoperative eGFR yielded a higher predictive accuracy for predicting eGFR6m <60 than that with preoperative eGFR alone {area under the receiver operating characteristic curve=0.886 [95% confidence interval (CI), 0.863-0.908] vs. 0.862 (95% CI, 0.838-0.887), p<0.001}. CONCLUSION: The incidence of eGFR6m <60 was 17.3%. Older age, lower preoperative eGFR, history of hypertension, and greater ΔCr2_pre were associated with the occurrence of eGFR6m <60 after living donor nephrectomy. The combination of preoperative eGFR and ΔCr2_pre showed the highest predictive power for eGFR6m <60.

Histone deacetylase 1 maintains lineage integrity through histone acetylome refinement during early embryogenesis.

Histone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid-blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. Cis-regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation-deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.

Effects of arginase inhibition on myocardial Ca2+ and contractile responses.

Nitric oxide (NO) is thought to increase cardiac contractility by increasing cytosolic Ca2+ concentration ([Ca2+ ]cyt ) during excitation. Alternatively, NO could increase the sensitivity of the contractile response to [Ca2+ ]cyt (Ca2+ sensitivity). Arginase regulates NO production by competing with NO synthase (NOS), and thus, arginase inhibition should increase cardiac contractility by increasing NO production. We hypothesized that arginase inhibition increases cardiac contractility by increasing both [Ca2+ ]cyt and Ca2+ sensitivity. [Ca2+ ]cyt and contractile (sarcomere length [SL] shortening) responses to electrical stimulation were measured simultaneously in isolated rat cardiomyocytes using an IonOptix system. In the same cardiomyocytes, measurements were obtained at baseline, following 3-min exposure to an arginase inhibitor (S-[2-boronoethyl]-l-cysteine; BEC) and following 3-min exposure to BEC plus a NOS inhibitor (NG -nitro-l-arginine-methyl ester; l-NAME). These responses were compared to time-matched control cardiomyocytes that were untreated. Compared to baseline, BEC increased the amplitude and the total amount of evoked [Ca2+ ]cyt , and the extent and velocity of SL shortening in cardiomyocytes, whereas addition of l-NAME mitigated these effects. The [Ca2+ ]cyt at 50% contraction and relaxation were not different across treatment groups indicating no effect of BEC on Ca2+ sensitivity. The [Ca2+ ]cyt and SL shortening responses in time-matched controls did not vary with time. Arginase inhibition by BEC significantly increased the amplitude and the total amount of evoked [Ca2+ ]cyt , and the extent and velocity of SL shortening in cardiomyocytes, but did not affect Ca2+ sensitivity. These effects of BEC were mitigated by l-NAME. Together, these results indicate an effect of NO on [Ca2+ ]cyt responses that then increase the contractile response of cardiomyocytes.

Impact of preoperative nutritional scores on 1-year postoperative mortality in patients undergoing valvular heart surgery.

OBJECTIVE: Malnutrition is a well-recognized risk factor for poor prognosis and mortality. We investigated whether preoperative malnutrition diagnosed with objective nutritional scores affects 1-year mortality in patients undergoing valvular heart surgery. METHODS: In this retrospective cohort observational study, we evaluated the association among the Controlling Nutritional Status score, Prognostic Nutritional Index, and Geriatric Nutritional Risk Index with 1-year mortality in 1927 patients undergoing valvular heart surgery. We identified factors for mortality using multivariable Cox proportional hazard analysis and investigated the utility of nutritional scores for risk stratification. RESULTS: Malnutrition, as identified by a high Controlling Nutritional Status score and low Prognostic Nutritional Index and Geriatric Nutritional Risk Index, was significantly associated with higher 1-year mortality. Kaplan-Meier survival curve showed that mortality significantly increased as the severity of malnutrition increased (log-rank test, P < .001). The predicted discrimination (C-index) was 0.79 with the Controlling Nutritional Status score, 0.77 with the Prognostic Nutritional Index, and 0.73 with the Geriatric Nutritional Risk Index. Each nutritional index (Controlling Nutritional Status; hazard ratio, 1.31, 95% confidence interval, 1.21-1.42, P < .001), the European System for Cardiac Operative Risk Evaluation II (hazard ratio, 1.07, 95% confidence interval, 1.04-1.09, P < .001), and chronic kidney disease (hazard ratio, 2.26, 95% confidence interval, 1.31-3.90, P = .003) were independent risk factors for mortality. The Controlling Nutritional Status score added to the European System for Cardiac Operative Risk Evaluation II significantly increased the predictive discrimination ability for mortality (C-index 0.82, 95% confidence interval, 0.78-0.87, P = .014) compared with the Controlling Nutritional Status or European System for Cardiac Operative Risk Evaluation II alone. CONCLUSIONS: Preoperative malnutrition as assessed by objective nutritional scores was associated with 1-year mortality after valvular heart surgery. The Controlling Nutritional Status score had the highest predictive ability and, when added to the European System for Cardiac Operative Risk Evaluation II, provided more accurate risk stratification.

Uncovering the mesendoderm gene regulatory network through multi-omic data integration.

Mesendodermal specification is one of the earliest events in embryogenesis, where cells first acquire distinct identities. Cell differentiation is a highly regulated process that involves the function of numerous transcription factors (TFs) and signaling molecules, which can be described with gene regulatory networks (GRNs). Cell differentiation GRNs are difficult to build because existing mechanistic methods are low throughput, and high-throughput methods tend to be non-mechanistic. Additionally, integrating highly dimensional data composed of more than two data types is challenging. Here, we use linked self-organizing maps to combine chromatin immunoprecipitation sequencing (ChIP-seq)/ATAC-seq with temporal, spatial, and perturbation RNA sequencing (RNA-seq) data from Xenopus tropicalis mesendoderm development to build a high-resolution genome scale mechanistic GRN. We recover both known and previously unsuspected TF-DNA/TF-TF interactions validated through reporter assays. Our analysis provides insights into transcriptional regulation of early cell fate decisions and provides a general approach to building GRNs using highly dimensional multi-omic datasets.

Effects of Perioperative Dexmedetomidine on Immunomodulation in Uterine Cancer Surgery: A Randomized, Controlled Trial.

OBJECTIVE: Dexmedetomidine has sympatholytic, anti-inflammatory, and analgesic effects and may exert anti-tumor effect by acting on α2A adrenoreceptor. We investigated whether perioperative dexmedetomidine preserves immune function in patients undergoing uterine cancer surgery. METHODS: One hundred patients were randomly assigned to the control or dexmedetomidine groups (50 patients each). Dexmedetomidine was infused at rates of 0.4 µg/kg/h intraoperatively and 0.15 µg/kg/h during the first 24 h postoperatively. The primary outcome was natural killer (NK) cell activity, which was measured preoperatively and 1, 3, and 5 days postoperatively. The inflammatory response was measured by interleukin-6, interferon-γ, and neutrophil/lymphocyte ratio, and pain scores and opioid consumption were assessed. Cancer recurrence or metastasis and death were evaluated 2 years postoperatively. RESULTS: NK cell activity decreased postoperatively in both groups and changes over time were not different between groups (P=0.496). Interferon-γ increased postoperatively in the dexmedetomidine group, whereas it maintained at the baseline value in the control group. Change in interferon-γ differed significantly between groups (P=0.003). Changes in interleukin-6 and neutrophil-lymphocyte ratio were comparable between groups. Both pain score with activity during the first 1 h and opioid consumption during the first 1-24 h postoperatively were lower in the dexmedetomidine group. Rates of cancer recurrence/metastasis (16.3% vs. 8.7%, P=0.227) and death within 2 years postoperatively (6.7% vs. 2.2%, P=0.318) were not different between groups. CONCLUSIONS: Perioperative dexmedetomidine had no favorable impacts on NK cell activity, inflammatory responses, or prognosis, whereas it increased interferon-γ and reduced early postoperative pain severity and opioid consumption in uterine cancer surgery patients.