The Effects of Volatile Anesthetics on Lung Ischemia-Reperfusion Injury: Basic to Clinical Studies.

Case reports from as early as the 1970s have shown that intravenous injection of even a small dose of volatile anesthetics result in fatal lung injury. Direct contact between volatile anesthetics and pulmonary vasculature triggers chemical damage in the vessel walls. A wide variety of factors are involved in lung ischemia-reperfusion injury (LIRI), such as pulmonary endothelial cells, alveolar epithelial cells, alveolar macrophages, neutrophils, mast cells, platelets, proinflammatory cytokines, and surfactant. With a constellation of factors involved, the assessment of the protective effect of volatile anesthetics in LIRI is difficult. Multiple animal studies have reported that with regards to LIRI, sevoflurane demonstrates an anti-inflammatory effect in immunocompetent cells and an anti-apoptotic effect on lung tissue. Scattered studies have dismissed a protective effect of desflurane against LIRI. While a single-center randomized controlled trial (RCT) found that volatile anesthetics including desflurane demonstrated a lung-protective effect in thoracic surgery, a multicenter RCT did not demonstrate a lung-protective effect of desflurane. LIRI is common in lung transplantation. One study, although limited due to its small sample size, found that the use of volatile anesthetics in organ procurement surgery involving "death by neurologic criteria" donors did not improve lung graft survival. Future studies on the protective effect of volatile anesthetics against LIRI must examine not only the mechanism of the protective effect but also differences in the effects of different types of volatile anesthetics, their optimal dosage, and the appropriateness of their use in the event of marked alveolar capillary barrier damage.

Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor α, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.

A Rare Duodenal Carcinosarcoma: A Case Report and Literature Review.

Carcinosarcoma is a biphasic malignant tumor comprising both carcinomatous and sarcomatous components; its occurrence in the duodenum is very rare. We herein report the case of a 96-year-old woman with duodenal carcinosarcoma showing rapid growth within the past year. The tumor was found to be bulging into the lumen and predominantly comprised sarcomatoid components with focal positive staining for cytokeratin. Therefore, the tumor was diagnosed as duodenal carcinosarcoma. The clinical information of the present case and our literature review of the 12 cases reported to date will help physicians diagnose and treat this rare tumor.

Desflurane inhalation before ischemia increases ischemia-reperfusion-induced vascular leakage in isolated rabbit lungs.

BACKGROUND: Isoflurane and sevoflurane protect lungs with ischemia-reperfusion (IR) injury. We examined the influence of desflurane on IR lung injury using isolated rabbit lungs perfused with a physiological salt solution. METHODS: The isolated lungs were divided into three groups: IR, desflurane-treated ischemia-reperfusion (DES-IR), and ventilation/perfusion-continued control (Cont) groups (n = 6 per group). In the DES-IR group, inhalation of desflurane at 1 minimum alveolar concentration (MAC) was conducted in a stable 30-min phase. In the IR and DES-IR groups, ventilation/perfusion was stopped for 75 min after the stable phase. Subsequently, they were resumed. Each lung was placed on a balance, and weighed. Weight changes were measured serially throughout this experiment. The coefficient of filtration (Kfc) was determined immediately before ischemia and 60 min after reperfusion. Furthermore, bronchoalveolar lavage fluid (BALF) was collected from the right bronchus at the completion of the experiment. After the completion of the experiment, the left lung was dried, and the lung wet-to-dry weight ratio (W/D) was calculated. RESULTS: The Kfc values at 60 min after perfusion were 0.40 ± 0.13 ml/min/mmHg/100 g in the DES-IR group, 0.26 ± 0.07 ml/min/mmHg/100 g in the IR group, and 0.22 ± 0.08 (mean ± SD) ml/mmHg/100 g in the Cont group. In the DES-IR group, the Kfc at 60 min after the start of reperfusion was significantly higher than in the other groups. In the DES-IR group, W/D was significantly higher than in the Cont group. In the DES-IR group, the BALF concentrations of nitric oxide metabolites were significantly higher than in the other groups. In the DES-IR group, the total amount of vascular endothelial growth factor in BALF was significantly higher than in the Cont group. CONCLUSIONS: The pre-inhalation of desflurane at 1 MAC exacerbates pulmonary IR injury in isolated/perfused rabbit lungs.

Prognostic impact of clinical course-specific mRNA expression profiles in the serum of perioperative patients with esophageal cancer in the ICU: a case control study.

BACKGROUND: We previously reported that measuring circulating serum mRNAs using quantitative one-step real-time RT-PCR was clinically useful for detecting malignancies and determining prognosis. The aim of our study was to find crucial serum mRNA biomarkers in esophageal cancer that would provide prognostic information for post-esophagectomy patients in the critical care setting. METHODS: We measured serum mRNA levels of 11 inflammatory-related genes in 27 post-esophagectomy patients admitted to the intensive care unit (ICU). We tracked these levels chronologically, perioperatively and postoperatively, until the two-week mark, investigating their clinical and prognostic significance as compared with clinical parameters. Furthermore, we investigated whether gene expression can accurately predict clinical outcome and prognosis. RESULTS: Circulating mRNAs in postoperative esophagectomy patients had gene-specific expression profiles that varied with the clinical phase of their treatment. Multivariate regression analysis showed that upregulation of IL-6, VWF and TGF-ß1 mRNA in the intraoperative phase (p = 0.016, 0.0021 and 0.009) and NAMPT and MUC1 mRNA on postoperative day 3 (p < 0.01) were independent factors of mortality in the first year of follow-up. Duration of ventilator dependence (DVD) and ICU stay were independent factors of poor prognosis (p < 0.05). Therapeutic use of Sivelestat (Elaspol®, Ono Pharmaceutical Co., Ltd.) significantly correlated with MUC1 and NAMPT mRNA expression (p = 0.048 and 0.045). IL-6 mRNA correlated with hypercytokinemia and recovery from hypercytokinemia (sensitivity 80.9%) and was a significant biomarker in predicting the onset of severe inflammatory diseases. CONCLUSION: Chronological tracking of postoperative mRNA levels of inflammatory-related genes in esophageal cancer patients may facilitate early institution of pharamacologic therapy, prediction of treatment response, and prognostication during ICU management in the perioperative period.

Effect of intraoperative acetated Ringer's solution with 1% glucose on glucose and protein metabolism.

PURPOSE: To investigate the effects of the intraoperative administration of Ringer's solution with 1% glucose on the metabolism of glucose, lipid and muscle protein during surgery. METHODS: Thirty-one adult patients, American Society of Anesthesiologists physical status I or II, undergoing elective otorhinolaryngeal, head and neck surgeries were randomly assigned to one of two patient groups: those receiving acetated Ringer's solution with 1% glucose (Group G) or those receiving acetated Ringer's solution without glucose (Group R) throughout the surgical procedure. Plasma glucose was measured at anesthetic induction (T0), artery 1 h (T1), 2 h (T2), 3 h after anesthetic induction (T3) and at the end of surgery (T4). Plasma ketone bodies, insulin and 3-methylhistidine were measured at T0 and T4. RESULTS: The intravenous infusion for patients in Group G and R was 6.1 + or - 0.8 and 6.3 + or - 1.7 ml/kg/h, respectively, with Group G patients receiving a dose of 4.1 g/h glucose. Plasma glucose levels were significantly higher in Group G than in Group R patients at T1, T2, T3 and T4; however, plasma glucose remained <150 mg/dl in both groups. The plasma concentration of ketone bodies was significantly higher (P < 0.05) in Group R than in Group G patients at T4. Changes in plasma 3-methylhistidine concentration was significantly lower in Group G than in Group R patients. These results indicate that acetated Ringer's solution with 1% glucose decreased protein catabolism without hyperglycemia among the Group G patients. CONCLUSION: The infusion of a small dose of glucose (1%) during minor otorhinolaryngeal, head and neck surgeries may suppress protein catabolism without hyperglycemia and hypoglycemia.

Caudal blockade shortens the time to walking exercise in elderly patients following low back surgery.

PURPOSE: We conducted a randomized, double-blinded study to test our hypothesis that caudal blockade as preemptive analgesia for low back surgery might accelerate time to walking exercise following surgery and reduce postoperative analgesics, thereby attaining faster recovery of cognitive function. METHODS: Our study included 51 elderly patients >70 years with American Society of Anesthesiologists (ASA) physical status 1-3, who underwent lumbosacral surgery under general anesthesia. After anesthetic induction and tracheal intubation, patients in the study group (group B) were injected with simple 0.5% bupivacaine [10 ml x height (m)] as a caudal block 15 min before surgical incision, whereas patients in the control group (group C) received normal saline. After surgery, patients had access to intravenous patient-administered analgesia (IV PCA), fentanyl, for postoperative pain relief. We assessed Mini-Mental State Examination (MMSE) scores before and after the surgery, values of visual analog scale (VAS) for postoperative analgesic status, fentanyl consumption during and for 3 days after surgery, and time to begin walking exercise after surgery. RESULTS: VAS value of group B patients was significantly lower than those in group C throughout the postoperative 48-h period (p < 0.005), and group B patients began walking exercise significantly earlier than those in group C [mean +/- standard deviation (SD) 70.2 (14.3) in group C, and 61.9 (7.6) in group B; p = 0.0133]. Cognitive function level was higher in group B than in group C patients 24 h after operation. CONCLUSIONS: Caudal blockade as preemptive analgesia shortened the time to start walking exercise after surgery and accelerated recovery of postoperative cognitive function.

A noncoding RNA gene on chromosome 10p15.3 may function upstream of hTERT.

BACKGROUND: We attempted to clone candidate genes on 10p 14-15 which may regulate hTERT expression, through exon trapping using 3 BAC clones covering the region. After obtaining 20 exons, we examined the function of RGM249 (RGM: RNA gene for miRNAs) we cloned from primary cultured human hepatocytes and hepatoma cell lines. We confirmed approximately 20 bp products digested by Dicer, and investigated the function of this cloned gene and its involvement in hTERT expression by transfecting the hepatoma cell lines with full-length dsRNA, gene-specific designed siRNA, and shRNA-generating plasmid. RESULTS: RGM249 showed cancer-dominant intense expression similar to hTERT in cancer cell lines, whereas very weak expression was evident in human primary hepatocytes without telomerase activity. This gene was predicted to be a noncoding precursor RNA gene. Interestingly, RGM249 dsRNA, siRNA, and shRNA inhibited more than 80% of hTERT mRNA expression. In contrast, primary cultured cells overexpressing the gene showed no significant change in hTERT mRNA expression; the overexpression of the gene strongly suppressed hTERT mRNA in poorly differentiated cells. CONCLUSION: These findings indicate that RGM249 might be a microRNA precursor gene involved in the differentiation and function upstream of hTERT.

Clinical impact of serum transforming growth factor-alpha mRNA as a predictive biomarker for the prognosis of fulminant hepatitis.

PURPOSE: We previously reported that measuring serum telomerase reverse transcriptase (hTERT) mRNA with a quantitative, one-step, real-time RT-PCR was superior to conventional tumor markers for hepatocellular carcinoma and lung cancer. Here, we examined serum regeneration-related mRNA detection as a biomarker for fulminant hepatitis (FH). METHODS: In 53 patients, including 17 patients with acute hepatitis (AH), seven with severe hepatitis (SH), four with late-onset hepatic failure (LOHF), and 25 with FH, we measured serum mRNA levels of hTERT, hepatocyte growth factor (HGF), hepatocyte growth factor receptor (c-met), epidermal growth factor receptor (EGFR), and transforming growth factor-alpha (TGF-alpha). We examined the sensitivity and specificity of the technique in FH diagnosis as well as its clinical and prognostic significance compared with other clinical and prognostic tests. RESULTS: Serum copy number of TGF-alpha mRNA in FH on admission was significantly smaller than in AH and SH. In FH, TGF-alpha mRNA level was 10(6)-fold higher in survivors than in patients who died or received liver transplants (P = 0.034), although these patients were not discriminated by other clinical parameters. The sensitivity/specificity for prognosis in FH was 74.3/65.5% for TGF-alpha mRNA. Of four prognostic scoring systems, only logit-lambda was useful for prognosis assessment. CONCLUSIONS: TGF-alpha mRNA is an early predictor of FH outcome and a sensitive biomarker of lower regenerative liver capacity. This assay could help facilitate early therapy choice, such as liver transplantation.

A diagnostic evaluation of serum human telomerase reverse transcriptase mRNA as a novel tumor marker for gynecologic malignancies.

Human telomerase reverse transcriptase (hTERT) and epidermal growth factor receptor (EGFR) play an important role in many cancers including gynecological cancers. We previously reported the usefulness of a quantitative highly sensitive detection method for hTERT mRNA in the serum of cancer patients. By this method, we attempted to elucidate the diagnostic evaluation of serum hTERT mRNA for gynecologic malignancies. In 174 female patients with gynecological lesions (47 with ovarian lesions, 63 with uterine lesions, 2 with malignancies in other gynecological lesions, and 62 benign lesions) and 20 healthy individuals, we measured serum hTERT mRNA and EGFR mRNA by using the newly developed real-time quantitative RT-PCR. We examined their sensitivity and specificity in cancer diagnosis, clinical significance in comparison with conventional tumor markers, and their correlations with the clinical parameters by using multivariate analyses. Serum hTERT mRNA showed higher values in patients with gynecologic cancers than in those with benign diseases and healthy individuals. The hTERT mRNA level independently correlated with the presence of cancers (P=0.004 for both ovarian and uterine cancer) and clinical stage (P<0.001). The sensitivity and specificity of hTERT mRNA in cancer diagnosis was 74.4% and 74.1%, respectively. The hTERT mRNA level showed a significant correlation with CA125 by Pearson's relative test (P=0.035) and with histological findings in ovarian cancer by the Friedman test (P<0.004). EGFR mRNA did not display any differences between the diseases. hTERT mRNA is useful for diagnosing gynecologic cancer and is superior to conventional tumor markers. Therefore, serum hTERT mRNA is a novel and available biomarker for gynecologic malignancies.

Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer.

Using a newly developed assay of telomerase reverse transcriptase (hTERT) mRNA in serum by real-time RT-PCR, we previously reported this assay to be superior to other tumor markers for hepatoma. In this study, we aimed to clarify its clinical significance as a biomarker for lung cancer. In 112 patients with lung tumor and 80 individuals without cancer, we measured serum hTERT mRNA and epidermal growth factor receptor (EGFR) mRNA levels, using a quantitative one-step real-time RT-PCR assay. We examined its sensitivity and specificity in lung cancer diagnosis, its clinical significance in comparison with other tumor markers, and its correlation with the clinical parameters using multivariate analyses and correlation relative tests. The copy number of serum hTERT mRNA was independently correlated with tumor size, tumor number, presence of metastasis and recurrence, and smoking (all P < 0.05). EGFR mRNA correlated with tumor number and clinical stage (both P < 0.05). The sensitivity and specificity in lung cancer diagnosis were 89.0% and 72.7% for hTERT mRNA, and 71.3% and 80.0% for EGFR mRNA, respectively. hTERT mRNA was superior to other tumor markers in lung cancer diagnosis. For both mRNAs, serum levels were significantly correlated with levels in lung cancer tissues (both P < 0.05). The copy number of hTERT mRNA significantly decreased after the surgical treatment. The data suggest that hTERT mRNA, especially when combined with EGFR mRNA, is a novel and excellent biomarker for pulmonary malignancies to diagnose and assess the clinical stage.