The effect of ulinastatin on acute kidney injury in patients undergoing off-pump cardiac bypass surgery.

BACKGROUND: Ulinastatin, an anti-inflammatory and antioxidant trypsin inhibitor, has shown potential in mitigating acute kidney injury (AKI) and reducing serum creatinine levels after various surgeries. This retrospective study aimed to evaluate the effects of ulinastatin on AKI in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. METHODS: We hypothesized that the administration of ulinastatin could prevent AKI in OPCAB. Electrical medical records were reviewed to identify OPCAB patients between January 2015 and June 2020. The utilization of ulinastatin was randomly determined and applied during this period. Acute kidney injury was defined according to the KDIGO guideline, and its incidence was compared between the ulinastatin administration group and the control group. To investigate the effect of ulinastatin on renal function, multivariate logistic regression analysis was used to calculate propensity scores for each group. RESULTS: A total 454 OPCAB were performed, and after following inclusion and exclusion process, 100 patients were identified in the ulinastatin group and 303 patients in the control group. Using 1:2 propensity score matching, we analyzed 100 and 200 patients in the ulinastatin and control groups. The incidence of AKI was similar between the groups (2.5% for the control group, 2.0% for the ulinastatin group, p > 0.999). However, the serum creatinine value on the first post-operative day were significantly lower in the ulinastatin group compared to the control group (0.774 ± 0.179 mg/dL vs 0.823 ± 0.216 mg/dL, P = 0.040), while no significant differences were observed for the other time points (P > 0.05). The length of ICU stay day was significantly shorter in the ulinastatin group (2.91 ± 2.81 day vs 5.22 ± 7.45 day, respectively, P < 0.001). CONCLUSIONS: Ulinastatin did not have a significant effect on the incidence of AKI; it demonstrated the ability to reduce post-operative serum creatine levels at first post-operative day and shorten the length of ICU stay.

Intravenous dexamethasone does not prolong the duration of pudendal nerve block in infants and children undergoing hypospadias surgery: A randomized clinical trial.

BACKGROUND: The administration of intravenous dexamethasone increases the duration of neuraxial block and improves the quality of analgesia. However, little is known about these effects of dexamethasone on peripheral nerve blocks in children. AIMS: In this study, we aimed to investigate the benefit of intravenous dexamethasone for enhancing the effect of pudendal block on postoperative analgesia in children who underwent hypospadias surgery. METHODS: In total, 46 children aged 6-36 months who underwent hypospadias surgery were randomly allocated to either a control group (normal saline, group C) or dexamethasone group (0.5 mg/kg, group D). Pudendal block was performed before the surgery using 0.3 mL/kg of 0.225% ropivacaine on both sides. Parents were instructed to press the patient-controlled analgesia bolus button when their children's pain score was >4 points. The primary outcome measure was the time at which the first patient-controlled analgesia by proxy bolus dose was administered. The secondary outcome measures were pain score, number of patient-controlled analgesia administration by proxy bolus attempts, number of rescue analgesics required, total amount of fentanyl administered, and overall parental satisfaction. RESULTS: The time of first patient-controlled analgesia bolus administration by proxy was not different between the control and dexamethasone groups (5.6 [5.2, 8.8] h versus 6.5 [5.4, 8.1] h, hazard ratio 0.8, 95% confidence intervals 0.43 to 1.47, p = .46). There were no statistically significant differences among the secondary outcomes. CONCLUSIONS: Administration of intravenous dexamethasone did not enhance the duration of pudendal nerve block in infants and children aged 6-36 months who underwent hypospadias surgery.

The Effect of Ramosetron on Remifentanil in Preventing Emergence Cough from Sevoflurane Anesthesia in Female Patients.

BACKGROUND: Remifentanil reduces cough during extubation. Ramosetron, a 5-HT3 receptor antagonist, is a potent antiemetic. Regarding the antitussive property of 5-HT receptor agonists, ramosetron can mediate the cough reflex by increasing the remifentanil requirement. This study evaluated the effect of ramosetron on the optimal effect-site concentration (Ce) of remifentanil for preventing emergence cough from sevoflurane anesthesia in female patients. METHODS: Forty-seven randomly selected female patients undergoing laparoscopic cholecystectomy received either ramosetron 0.3 mg (n = 23) or the same volume of normal saline (n = 24) intravenously at the end of surgery. The remifentanil Ce using target-controlled infusion in 50% of patients (EC50) and 95% of patients (EC95) were assessed using Dixon's up-and-down or isotonic regression method with a bootstrapping approach. RESULTS: Using Dixon's up-and-down method, the EC50 of remifentanil in the control group (1.33 ± 0.38 ng/mL) was comparable to that of ramosetron group (1.50 ± 0.69 ng/mL) (P = 0.615). Using isotonic regression analysis, the EC50 (83% confidence interval) did not differ between the two groups (1.17 [0.86-1.43] ng/mL and 1.13 [0.68-1.56] ng/mL in control and ramosetron groups). However, the EC95 (95% confidence interval) was significantly lower in the control group than in the ramosetron group (1.90 [1.45-1.96] ng/mL and 2.92 [2.35-2.97] ng/mL). CONCLUSION: Remifentanil Ce for preventing emergence cough was higher in the ramosetron group than in the control group. It may indicate the lowering effect of ramosetron on the antitussive activity of remifentanil.

Association between nicotine dependency with occupational injury in Korean men.

BACKGROUND: The relationship between smoking status or second-hand smoking and occupational injuries has been the subject of considerable study, but few have studied the relationship between nicotine dependence and occupational injuries. The objective of this study was to investigate the relationship between nicotine dependence and occupational injury among employees at a range of Korean companies. METHODS: Initially, the personal and occupational characteristics and nicotine dependences of workers were measured, and 12 months later a survey was used to determine whether subjects had experienced any occupational injury. This study was conducted in several workplaces on 6,893 male workers in manufacturing and service industries that received health screening at Inha University Hospital in Incheon. RESULTS: The adjusted odds ratios (ORs) of occupational injury in the low, moderate, and high nicotine dependence groups were 1.38 (95% confidence interval [CI]: 1.04-1.84), 1.52 (95% CI: 1.10-2.10), and 1.71 (95% CI: 0.92-3.19), respectively. For smokers only, adjusted ORs tended to increase linearly (p for trend < 0.05). When only smokers were included, analysis of continuous FTND (Fagerstrom Test of Nicotine Dependence) scores showed that adjusted OR increased by 1.10 (95% CI: 1.03-1.19) per FTND point. After stratifying the data by working type and working hours per week, the non-shift work group maintained this relationship (OR: 1.13, 95% CI: 1.04-1.24) and OR was higher in the group that works more than 60 hours per week with FTND score as a continuous variable (OR: 1.24, 95% CI: 1.07-1.44). CONCLUSIONS: The study shows nicotine dependency might affect occupational injury. From a short-term perspective, addressing worker's nicotine dependence by giving an adequate break time or smoking area might reduce work-related injuries.

Clinical Utility of Combined Circulating Tumor Cell and Circulating Tumor DNA Assays for Diagnosis of Primary Lung Cancer.

BACKGROUND/AIM: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination. PATIENTS AND METHODS: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing. RESULTS: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type. CONCLUSION: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099).

Erratum: Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube.

This corrects the article on p. e43 in vol. 29, PMID: 29770616.

Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube.

OBJECTIVE: The aim of the present study was to assess the frequency of germline mutations in patients with peritoneal carcinoma (PC) or the fallopian tube carcinoma (FTC), using a multi-gene panel. METHODS: Twenty-six patients diagnosed with either PC or FTC between January 2013 and December 2016 were recruited consecutively. Germline DNA was sequenced using a 6-gene next generation sequencing (NGS) panel following genetic counseling. Surgico-medical information was obtained from hospital records. Genetic variations were detected using the panel and were cross-validated by Sanger direct sequencing. RESULTS: Germline BRCA1/2 mutations were identified in 6 patients (23.1%). Four were detected in patients with PC and 2 were in FTC patients. No mutations were detected in TP53, PTEN, CDH1, or PALB2. We identified 11 variant of uncertain significance (VUS) in 9 patients; 2 in BRCA1, 3 in BRCA2, 2 in TP53, and 4 in CDH1. We also detected a CDH1 c.2164+16->A VUS in 3 patients. CONCLUSION: The prevalence of germline BRCA1/2 mutations in patients with PC or FTC is comparable to that of BRCA1/2 mutations in epithelial ovarian cancer patients.

Novel antimitotic activity of 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) through the inhibition of tubulin polymerization.

The natural chalcones and their derivatives exhibit many biological activities, such as anti-inflammatory and antitumoral. However, the precise mechanisms of action of benzochalcone derivatives are currently unknown. Here, a set of benzochalcones was synthesized, and the molecular mechanisms underlying inhibition of tumor growth were investigated. Colony-forming assays revealed that among tested compounds, 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) most effectively inhibited the clonogenicity of Capan-1 human pancreatic cancer cells. HymnPro inhibited cell proliferation in several human solid tumor cell lines and suppressed xenografted tumor growth in nude mice. Mechanistically, HymnPro induced cell cycle arrest at the G2/M phase, followed by an increase in apoptotic cell death. These events were associated with the inhibition of tubulin polymerization through binding of HymnPro to tubulin, leading to the formation of abnormal mono- or multipolar mitotic microtubule structures accompanied by spherical arrangement of multinucleated chromosomes. Furthermore, HymnPro activated caspase-2, caspase-9, caspase-3, and caspase-7 and increased the cleavage of poly(ADP-ribose) polymerase (PARP). HymnPro increased the phosphorylation of JNK1/2, Erk1/2, and p38 kinase. Pretreatment with SP600125, U0126, or SB600125 abrogated HymnPro-induced activation of caspases-3 and caspase-7 and the cleavage of PARP, suggesting that MAPK signalings are involved in HymnPro-induced apoptosis. It was concluded that a novel HymnPro compound exerts antitumor activity by disrupting microtubule assembly, which leads to mitotic arrest and sequential activation of the caspase pathway, resulting in apoptosis.

Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: a double blind, randomized clinical trial of efficacy and safety.

INTRODUCTION: Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double-blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery. METHODS: We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively. RESULTS: Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period. CONCLUSIONS: Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery. TRIAL REGISTRATION: Clinical Trial.gov, NCT01758861.

Erythropoietin prevents hypoxia-induced GATA-4 ubiquitination via phosphorylation of serine 105 of GATA-4.

Erythropoietin (EPO), an essential hormone for erythropoiesis, can provide protection against myocardial ischemia/reperfusion (I/R) injury and hypoxic apoptosis. GATA-4 is a zinc finger transcription factor, and its activation and post-translational modification are essential components in the transcriptional response to hypoxia. GATA-4 has also been reported to play a role in the cellular mechanisms of EPO-induced myocardial protection against I/R injury. In this study, we aimed to investigate the influence of EPO on GATA-4 protein stability and post-translational modification under hypoxic conditions without reperfusion. EPO induced cell viability under long-term hypoxia. EPO significantly increased phosphorylation of GATA-4 via the extracellular signal-regulated kinase (ERK) signaling pathway and reduced hypoxia-induced GATA-4 ubiquitination, which enhanced GATA-4 stability under hypoxia. ERK activation by over-expression of constitutively active mitogen-activated protein kinase 1 (MEK1) strongly increased GATA-4 phosphorylation and its protein levels and decreased GATA-4 ubiquitination under hypoxia. Despite ERK activation, GATA-4 ubiquitination was not affected under hypoxia in a GATA-4-S105A mutant. Under hypoxic condition without reperfusion, EPO-induced ERK activation was associated with post-translational modification of GATA-4, mediated by enhancement of phosphorylation of GATA-4 at Ser-105. Subsequent attenuation of GATA-4 ubiquitination led to increases in GATA-4 protein stability, which resulted in increased cell viability under hypoxia.

2'-Hydroxyflavanone induces apoptosis through Egr-1 involving expression of Bax, p21, and NAG-1 in colon cancer cells.

SCOPE: Natural flavanones exhibit cancer preventive and/or therapeutic effects. The objective of this study was to investigate the molecular mechanism underlying the action of the antitumor activity of hydroxyflavanone using the HCT116 colon cancer cell line. METHODS AND RESULTS: We investigated the effect of hydroxyflavanones on antitumor activity. We found that 2'-hydroxyflavanone (2'-HF) potently inhibited the clonogenicity of HCT116 cells. 2'-HF triggered apoptosis in both wild-type and p53-null HCT116 cells, as revealed by DNA fragmentation and caspase activation. 2'-HF upregulated nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1) expression through induction of Egr-1. Silencing of NAG-1 or Egr-1 using small interfering RNA (siRNA) could attenuate 2'-HF-induced apoptosis. Egr-1 also upregulated the proapoptotic gene Bax and the cell cycle inhibitor p21. CONCLUSION: Dietary 2'-HF may possess antitumor activity against human colon cancer.

Predictable factors of histologic discrepancy of gastric cancer between the endoscopic forceps biopsy and endoscopic treatment specimen.

BACKGROUND/AIMS: Recently, variable gastrointestinal track tumors including early stage malignancies are treated by endoscopic procedure. However, the discrepancy of histologic diagnosis may sometimes exist between the pretreatment forceps biopsy results and those of post treatment specimen. So the prediction of malignant lesion is important in the aspect of treatment selection. In this study, we investigated the predictable factors of the histologic discrepancy through the clinical, endoscopic features of the lesion diagnosed as adenocarcinoma in the post-endoscopic treatment specimen after the adenoma was diagnosed by the endoscopic forceps biopsy. METHODS: From March 2005 to April 2009, 129 gastric tumor lesions (129 patients) which were not diagnosed as malignancy and treated with endoscopic procedure were enrolled retrospectively. We compared the pretreatment endoscopic forceps biopsy results and post-treatment specimen biopsy results, then, analyzed the tumor characteristics. RESULTS: Twenty-one cases (16.3%) were diagnosed as malignancy after endoscopic treatment. Especially, discrepancy occurred more frequently in depressed lesions than in flat or elevated lesions (41.7% vs. 13.7%, p=0.012), and in lesions diagnosed as high grade adenomas than low or moderate grade adenomas (33.3% vs. 11.1%. p=0.004). CONCLUSIONS: In cases of depressed type lesions in the pretreatment endoscopy or those diagnosed as high grade adenoma in the pretreatment forceps biopsy, we should consider combined malignant lesion. Therefore, treatment modalities ensuring accurate diagnosis and potentially curative resection, should be carefully selected and performed in cases which have these features.

A case of portal vein thrombosis by protein C and s deficiency completely recanalized by anticoagulation therapy.

Portal vein thrombosis (PVT) is a rare form of venous thrombosis that affects the hepatic portal vein flow, which can lead to portal hypertension. Treatment of PVT includes anticoagulants, thrombolysis, insertion of shunts, bypass surgery, and liver transplantation. Single anticoagulation therapy is not regarded as a curative treatment but can be associated with a reduction in new thrombotic episodes. We experienced a case of acute total occlusion of PVT provoked by protein C and S deficiency syndrome. PVT was completely recanalized with oral anticoagulant therapy following low molecular weight heparin therapy.

Transcription factor Egr-1 is essential for maximal matrix metalloproteinase-9 transcription by tumor necrosis factor alpha.

Matrix metalloproteinase-9 (MMP-9) is involved in a wide range of normal and pathologic conditions, including inflammation, tissue repair, tumor invasion, and metastasis. Tumor necrosis factor alpha (TNFalpha) is a major proinflammatory cytokine that plays crucial roles in tumor progression, including tumor invasion and metastasis in the tumor microenvironment. Egr-1 is a member of the zinc-finger transcription factor family induced by diverse stimuli, including TNFalpha. However, the role of Egr-1 in MMP-9 expression was previously unknown. This study shows that Egr-1 directly binds to the MMP-9 promoter and plays an essential role for TNFalpha induction of MMP-9 transcription. Furthermore, Egr-1 together with NF-kappaB can synergistically activate both basal and TNFalpha-induced MMP-9 promoter activities in the presence of p300. We found that Egr-1 mediates extracellular signal-regulated kinase and c-jun NH(2)-terminal kinase mitogen-activated protein kinase-dependent MMP-9 transcription on TNFalpha stimulation. The requirement for Egr-1 in MMP-9 expression is further supported by the fact that HeLa cells expressing Egr-1 siRNA and Egr-1-null mouse embryonic fibroblasts were refractory to TNFalpha-induced MMP-9 expression. This report establishes that Egr-1 is essential for MMP-9 transcription in response to TNFalpha within the tumor microenvironment.