Driving pressure-guided ventilation and postoperative pulmonary complications in thoracic surgery: a multicentre randomised clinical trial.

BACKGROUND: Airway driving pressure, easily measured as plateau pressure minus PEEP, is a surrogate for alveolar stress and strain. However, the effect of its targeted reduction remains unclear. METHODS: In this multicentre trial, patients undergoing lung resection surgery were randomised to either a driving pressure group (n=650) receiving an alveolar recruitment/individualised PEEP to deliver the lowest driving pressure or to a conventional protective ventilation group (n=650) with fixed PEEP of 5 cm H2O. The primary outcome was a composite of pulmonary complications within 7 days postoperatively. RESULTS: The modified intention-to-treat analysis included 1170 patients (mean [standard deviation, sd]; age, 63 [10] yr; 47% female). The mean driving pressure was 7.1 cm H2O in the driving pressure group vs 9.2 cm H2O in the protective ventilation group (mean difference [95% confidence interval, CI]; -2.1 [-2.4 to -1.9] cm H2O; P<0.001). The incidence of pulmonary complications was not different between the two groups: driving pressure group (233/576, 40.5%) vs protective ventilation group (254/594, 42.8%) (risk difference -2.3%; 95% CI, -8.0% to 3.3%; P=0.42). Intraoperatively, lung compliance (mean [sd], 42.7 [12.4] vs 33.5 [11.1] ml cm H2O-1; P<0.001) and Pao2 (median [inter-quartile range], 21.5 [14.5 to 30.4] vs 19.5 [13.5 to 29.1] kPa; P=0.03) were higher and the need for rescue ventilation was less frequent (6.8% vs 10.8%; P=0.02) in the driving pressure group. CONCLUSIONS: In lung resection surgery, a driving pressure-guided ventilation improved pulmonary mechanics intraoperatively, but did not reduce the incidence of postoperative pulmonary complications compared with a conventional protective ventilation. CLINICAL TRIAL REGISTRATION: NCT04260451.

Antitumor activity of a lectibody targeting cancer-associated high-mannose glycans.

Aberrant protein glycosylation is a hallmark of cancer, but few drugs targeting cancer glycobiomarkers are currently available. Here, we showed that a lectibody consisting of the high-mannose glycan-binding lectin Avaren and human immunoglobulin G1 (IgG1) Fc (AvFc) selectively recognizes a range of cell lines derived from lung, breast, colon, and blood cancers at nanomolar concentrations. Binding of AvFc to the non-small cell lung cancer (NSCLC) cell lines A549 and H460 was characterized in detail. Co-immunoprecipitation proteomics analysis revealed that epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) are among the lectibody's common targets in these cells. AvFc blocked the activation of EGFR and IGF1R by their respective ligands in A549 cells and inhibited the migration of A549 and H460 cells upon stimulation with EGF and IGF1. Furthermore, AvFc induced potent Fc-mediated cytotoxic effects and significantly restricted A549 and H460 tumor growth in severe combined immunodeficiency (SCID) mice. Immunohistochemistry analysis of primary lung tissues from NSCLC patients demonstrated that AvFc preferentially binds to tumors over adjacent non-tumor tissues. Our findings provide evidence that increased abundance of high-mannose glycans in the glycocalyx of cancer cells can be a druggable target, and AvFc may provide a new tool to probe and target this tumor-associated glycobiomarker.

Effect of permissive hypercarbia on lung oxygenation during one-lung ventilation and postoperative pulmonary complications in patients undergoing thoracic surgery: A prospective randomised controlled trial.

BACKGROUND: The effect of hypercarbia on lung oxygenation during thoracic surgery remains unclear. OBJECTIVE: To investigate the effect of hypercarbia on lung oxygenation during one-lung ventilation in patients undergoing thoracic surgery and evaluate the incidence of postoperative pulmonary complications. DESIGN: Prospective randomised controlled trial. SETTING: A tertiary university hospital in the Republic of Korea from November 2019 to December 2020. PATIENTS: Two hundred and ninety-seven patients with American Society of Anaesthesiologists physical status II to III, scheduled to undergo elective lung resection surgery. INTERVENTION: Patients were randomly assigned to Group 40, 50, or 60. An autoflow ventilation mode with a lung protective ventilation strategy was applied to all patients. Respiratory rate was adjusted to maintain a partial pressure of arterial carbon dioxide of 40 ±â€Š5 mmHg in Group 40, 50 ±â€Š5 mmHg in Group 50 and 60 ±â€Š5 mmHg in Group 60 during one-lung ventilation and at the end of surgery. MAIN OUTCOME MEASURES: The primary outcome was the arterial oxygen partial pressure/fractional inspired oxygen ratio after 60 min of one-lung ventilation. RESULTS: Data from 262 patients were analysed. The partial pressure/fractional inspired oxygen ratio was significantly higher in Group 50 and Group 60 than in Group 40 (269.4 vs. 262.9 vs. 214.4; P  < 0.001) but was not significantly different between Group 50 and Group 60. The incidence of postoperative pulmonary complications was comparable among the three groups. CONCLUSION: Permissive hypercarbia improved lung oxygenation during one-lung ventilation without increasing the risk of postoperative pulmonary complications or the length of hospital stay. TRIAL REGISTRATION: NCT04175379.

Comparison of high flow nasal oxygen and conventional nasal cannula during gastrointestinal endoscopic sedation in the prone position: a randomized trial.

PURPOSE: Deep sedation for endoscopic retrograde cholangiopancreatography (ERCP) can be challenging in elderly patients in the prone position. This study investigated the effect of a high flow nasal oxygen (HFNO) delivery system on oxygenation in this procedure compared with that of conventional nasal cannula oxygen administration. METHODS: A prospective randomized trial was conducted using HFNO and conventional nasal cannula in patients undergoing ERCP in the prone position. For each patient, the lowest oxygen saturation (SpO2), the incidence of hypoxemia defined as an SpO2 below 90%, and interruptions due to airway interventions were recorded during the procedure. RESULTS: The lowest mean (standard deviation) SpO2 recorded during the procedure was higher in the HFNO group than in the conventional control group [99.8 (0.6)% vs 95.1 (7.3)%; mean difference, 4.7%; 95% confidence interval, 2.3% to 7.1%; P Group x Time < 0.001]. While the lowest SpO2 during the procedure was lower than the baseline SpO2 in the control group, the lowest SpO2 during the procedure was higher than the baseline SpO2 in the HFNO group. Hypoxemia occurred only in the control group (n = 7; 19%; P = 0.01). Procedural interruptions, including discontinuation of sedation, patient stimulation, and jaw thrusting, occurred only in the control group (n = 9 [25%], n = 10 [28%], and n = 10 [28%] cases, respectively; P = 0.001 for each). CONCLUSION: In contrast to conventional nasal cannula, high flow nasal oxygen provided adequate oxygenation without causing procedural interruptions during ERCP, suggesting that HFNO may be used as a standard oxygen delivery method during these procedures. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT03872674); registered 11 March 2019.

RéSUMé: OBJECTIF: La sédation profonde pour cholangiopancréatographie rétrograde endoscopique (CPRE) peut être difficile à réaliser chez des patients âgés en position ventrale. Cette étude a exploré l'effet d'un système d'oxygénothérapie nasale à haut débit (ONHD) sur l'oxygénation pendant cette intervention par rapport à l'administration conventionnelle d'oxygène via une lunette nasale. MéTHODE: Une étude randomisée prospective a été réalisée en utilisant une ONHD ou une lunette nasale conventionnelle chez des patients subissant une CPRE en position ventrale. Pour chaque patient, la saturation en oxygène (SpO2) la plus basse, l'incidence d'hypoxémie définie en tant qu'une SpO2 inférieure à 90 %, et les interruptions provoquées par des interventions au niveau des voies aériennes ont été enregistrées au cours de l'intervention. RéSULTATS: La SpO2 moyenne (écart type) la plus basse enregistrée pendant l'intervention était plus élevée dans le groupe ONHD que dans le groupe témoin conventionnel [99,8 (0,6) % vs 95,1 (7,3) %; différence moyenne, 4,7%; intervalle de confiance 95 %, 2,3 % à 7,1 %; P Groupe x Temps < 0,001]. Alors que la SpO2 la plus basse pendant l'intervention était plus basse que la SpO2 de base dans le groupe témoin, la SpO2 la plus basse pendant l'intervention était plus élevée que la SpO2 de base dans le groupe ONHD. L'hypoxémie n'est survenue que dans le groupe témoin (n = 7; 19 %; P = 0,01). Il n'y a eu d'interruptions de l'intervention, y compris la cessation de la sédation, la stimulation du patient et le déplacement de la mâchoire inférieure vers l'avant, que dans le groupe témoin (n = 9 [25 %], n = 10 [28 %], et n = 10 [28 %] cas, respectivement; P = 0,001 pour chaque intervention). CONCLUSION: Comparativement à une lunette nasale conventionnelle, l'oxygénothérapie nasale à haut débit a procuré une oxygénation adéquate sans provoquer d'interruptions de l'intervention pendant une CPRE, suggérant que cette modalité pourrait être utilisée comme méthode standard d'oxygénothérapie pendant de telles interventions. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT03872674); enregistrée le 11 mars 2019.

A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response.

Cholera toxin B subunit (CTB) exhibits broad-spectrum biologic activity upon mucosal administration. Here, we found that a recombinant CTB containing an endoplasmic reticulum (ER) retention motif (CTB-KDEL) induces colon epithelial wound healing in colitis via the activation of an unfolded protein response (UPR) in colon epithelial cells. In a Caco2 cell wound healing model, CTB-KDEL, but not CTB or CTB-KDE, facilitated cell migration via interaction with the KDEL receptor, localization in the ER, UPR activation, and subsequent TGF-ß signaling. Inhibition of the inositol-requiring enzyme 1/X-box binding protein 1 arm of UPR abolished the cell migration effect of CTB-KDEL, indicating that the pathway is indispensable for the activity. CTB-KDEL's capacity to induce UPR and epithelial restitution or wound healing was corroborated in a dextran sodium sulfate-induced acute colitis mouse model. Furthermore, CTB-KDEL induced a UPR, up-regulated wound healing pathways, and maintained viable crypts in colon explants from patients with inflammatory bowel disease (IBD). In summary, CTB-KDEL exhibits unique wound healing effects in the colon that are mediated by its localization to the ER and subsequent activation of UPR in epithelial cells. The results provide implications for a novel therapeutic approach for mucosal healing, a significant unmet need in IBD treatment.-Royal, J. M., Oh, Y. J., Grey, M. J., Lencer, W. I., Ronquillo, N., Galandiuk, S., Matoba, N. A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response.

Femoral neuropathy following venoarterial-extracorporeal membrane oxygenation therapy: a case report.

BACKGROUND: Although life-threatening complications of extracorporeal membrane oxygenation (ECMO) are well described, non-life threatening complications are less known. Herein, we report a case of femoral neuropathy (FN) due to nerve compression caused by cannula compression and deep vein thrombosis (DVT) after successful ECMO therapy, which seriously undermined one's quality of life. CASE PRESENTATION: A 70-year old male presented to the emergency department for chest pain. The patient had cardiac arrest before percutaneous coronary intervention (PCI) and was inserted with ECMO. Although he was successfully weaned from ECMO 4 days after PCI, he consistently complained swelling, abnormal sensation, and weakness in his right lower extremity, where the cannulas were inserted. Imaging studies showed deep vein thrombosis (DVT) in his right leg, which was further treated with anticoagulants. Symptoms, however, remained after the regression of DVT. Nerve conduction study revealed femoral neuropathy, which may have been caused by ECMO cannula compression and tissue swelling. CONCLUSION: The current case proposes that non-life threatening complications of ECMO therapy can seriously affect quality of life. Venous drainage distant from the arterial cannula may prevent such complications.

Effects of Inhaled Iloprost on Lung Mechanics and Myocardial Function During One-Lung Ventilation in Chronic Obstructive Pulmonary Disease Patients Combined With Poor Lung Oxygenation.

BACKGROUND: The ventilation/perfusion mismatch in chronic obstructive pulmonary disease (COPD) patients can exacerbate cardiac function as well as pulmonary oxygenation. We hypothesized that inhaled iloprost can ameliorate pulmonary oxygenation with lung mechanics and myocardial function during one-lung ventilation (OLV) in COPD patients combined with poor lung oxygenation. METHODS: A total of 40 patients with moderate to severe COPD, who exhibited the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FIO2) <150 mm Hg 30 minutes after initiating OLV, were enrolled in this study. Patients were randomly allocated into either ILO group (n = 20) or Control group (n = 20), in which iloprost (20 µg) and saline were inhaled, respectively. The PaO2/FIO2 ratio, dead space, dynamic compliance, and tissue Doppler imaging with myocardial performance index (MPI) were assessed 30 minutes after initiating OLV (pre-Tx) and 30 minutes after completion of drug inhalation (post-Tx). Repeated variables were analyzed using a linear mixed-model between the groups. RESULTS: At pre-Tx, no differences were observed in measured parameters between the groups. At post-Tx, PaO2/FIO2 ratio (P < .001) and dynamic compliance (P = .023) were significantly higher and dead space ventilation was significantly lower (P = .001) in iloprost group (ILO group) compared to Control group. Left (P = .003) and right ventricular MPIs (P < .001) significantly decreased in ILO group compared to Control group. CONCLUSIONS: Inhaled iloprost improved pulmonary oxygenation, lung mechanics, and cardiac function simultaneously during OLV in COPD patients with poor lung oxygenation.

Efficacy of Ultrasound-Guided Serratus Plane Block on Postoperative Quality of Recovery and Analgesia After Video-Assisted Thoracic Surgery: A Randomized, Triple-Blind, Placebo-Controlled Study.

BACKGROUND: The optimal regional technique for analgesia and improved quality of recovery after video-assisted thoracic surgery (a procedure associated with considerable postoperative pain) has not been established. The main objective in this study was to compare quality of recovery in patients undergoing serratus plane block (SPB) with either ropivacaine or normal saline on the first postoperative day. Secondary outcomes were analgesic outcomes, including postoperative pain intensity and opioid consumption. METHODS: Ninety patients undergoing video-assisted thoracic surgery were randomized to receive ultrasound-guided SPB with 0.4 mL/kg of either 0.375% ropivacaine (SPB group) or normal saline (control group) after anesthetic induction. The primary outcome was the 40-item Quality of Recovery (QoR-40) score at 24 hours after surgery. The QoR-40 questionnaire was completed by patients the day before surgery and on postoperative days 1 and 2. Pain scores, opioid consumption, and adverse events were assessed for 2 days postoperatively. RESULTS: Eighty-five patients completed the study: 42 in the SPB group and 43 in the control group. The global QoR-40 scores on both postoperative days 1 and 2 were significantly higher in the SPB group than in the control group (estimated mean difference 8.5, 97.5% confidence interval [CI], 2.1-15.0, and P = .003; 8.5, 97.5% CI, 2.0-15.1, and P = .004, respectively). The overall mean difference between the SPB and control groups was 8.5 (95% CI, 3.3-13.8; P = .002). Pain scores at rest and opioid consumption were significantly lower up to 6 hours after surgery in the SPB group than in the control group. Cumulative opioid consumption was significantly lower up to 24 hours postoperatively in the SPB group. CONCLUSIONS: Single-injection SPB with ropivacaine enhanced the quality of recovery for 2 days postoperatively and improved postoperative analgesia during the early postoperative period in patients undergoing video-assisted thoracic surgery.

Efficacy of Palonosetron-Dexamethasone Combination Versus Palonosetron Alone for Preventing Nausea and Vomiting Related to Opioid-Based Analgesia: A Prospective, Randomized, Double-blind Trial.

Background: The efficacy of dexamethasone plus palonosetron for postoperative nausea and vomiting (PONV) prophylaxis is not firmly established. This randomized, double-blind, controlled study evaluated whether the combination was superior to palonosetron alone in preventing PONV in patients receiving intravenous patient-controlled analgesia (IV-PCA) after upper extremity surgery. Methods: A total of 202 patients undergoing upper extremity surgery were randomly assigned to group P (palonosetron alone) or group PD (palonosetron plus dexamethasone). Group P patients received palonosetron 0.075 mg and normal saline 1.6 mL; group PD patients received palonosetron 0.075 mg and dexamethasone 8 mg. In both groups, palonosetron was added to the IV-PCA opioid infusion, which was continued for 48 h postoperatively. Incidence and severity of nausea, incidence of vomiting, rescue antiemetic requirements, pain intensity, and rescue analgesic requirements were evaluated for 72 h postoperatively. Quality of recovery was assessed using the quality of recovery-15 (QoR-15) questionnaire. Results: The incidence of PONV was significantly lower in group PD than in group P at 0-48 h postoperatively (61.5% vs 77.1%; p = 0.019). Severity of nausea at 0-6 h postoperatively was significantly less in group PD compared with group P (none/mild/moderate/severe: 49/22/15/10 vs. 36/16/25/19, p = 0.008). The incidence of vomiting and rescue antiemetic requirements were similar between groups. Pain intensity was significantly less in group PD than in group P at 0-48 h and 48-72 h postoperatively. Global QoR-15 was similar 24 h postoperatively between groups. Conclusions: Dexamethasone-palonosetron combination therapy reduced PONV incidence and postoperative pain in patients receiving opioid-based analgesia after upper extremity surgery.

Role of tissue transglutaminase in age-associated ventricular stiffness.

Aging is associated with increased cardiomyocyte loss, left-ventricular hypertrophy, and the accumulation of extracellular matrix, which results in declining cardiac function. The role of the matrix crosslinking enzyme, tissue transglutaminase (TG2), in age-related myocardial stiffness, and contractile function remains incompletely understood. In this study, we examined the role of TG2 in cardiac function, and determined whether TG2 inhibition can prevent age-associated changes in cardiac function. Male Fisher rats (18-month-old) were administered the transglutaminase inhibitor cystamine (study group) or saline (age-matched controls) for 12 weeks via osmotic mini-pumps. Cardiac function was determined by echocardiography and invasive pressure-volume loops. Rat hearts were dissected out, and TG2 expression, activity, and S-nitrosation were determined. Young (6-month-old) males were used as controls. TG2 activity significantly increased in the saline-treated but not in the cystamine-treated aging rat hearts. TG2 expression also increased with age and was unaltered by cystamine treatment. Aged rats showed increased left ventricular (LV) end-systolic dimension and a decrease in fractional shortening compared with young, which was not affected by cystamine. However, cystamine treatment preserved the preload-independent index of LV filling pressure and restored end-diastolic pressure, end-diastolic pressure-volume relationships, and arterial elastance toward young. An increase in TG2 activity contributes to age-associated increase in diastolic stiffness, thereby contributing to age-associated diastolic dysfunction. TG2 may thus represent a novel target for age-associated diastolic heart failure.

First principles study of the Mn-doping effect on the physical and chemical properties of mullite-family Al2SiO5.

Transition metal (TM) modification is a common strategy for converting an earth-abundant mineral into a cost-effective catalyst for industrial applications. Among a variety of minerals, Al2SiO5, which has three phases, andalusite, sillimanite and kyanite, is emerging as a promising candidate for new catalyst development. In this paper, we use Mn to demonstrate the rationale of 3d TM doping at the Al sites in each of these three phases through first-principles calculations and the cluster expansion method. The results of cluster expansion show that Mn has a strong site preference for the six-coordinated Al octahedral chains in the andalusite and sillimanite phases, while distributing randomly in the kyanite phase. Moreover, Mn can only replace Al in sillimanite and kyanite in low concentrations; however, higher concentrations of Mn can replace Al in andalusite. We found that the concentration sensitivity is due to the Jahn-Teller distortion and 3d orbital splitting. This finding can also explain the low doping concentrations of other 3d TMs (Fe, Cr and V) in Al2SiO5 compounds. Based on the calculated Helmholtz free energy, we constructed a (MnxAl1-x)AlSiO5 temperature-composite phase diagram, which explains the physical mechanisms behind the results for 3d transition metal doping and phase transitions in Al2SiO5. This work could shed light on the related physics, chemistry, and geoscience of (MnxAl1-x)AlSiO5, and more importantly, a design rationale for the engineering of cheap catalysts.

Assessment of dexmedetomidine effects on left ventricular function using pressure-volume loops in rats.

PURPOSE: The role of dexmedetomidine on left ventricular function is ambiguous. We analyzed pressure-volume loops to investigate whether dexmedetomidine has a myocardial depressive effect. METHODS: Thirty-two Sprague-Dawley rats were anesthetized and a pressure-volume loop catheter was advanced into the left ventricle. Rats were divided into four groups (n = 8 each). The control group received a 10-min infusion of 0.1 ml of normal saline, and the other three groups received 1.0 (Dex1.0 group) , 2.5 (Dex2.5 group), and 5.0 µg/kg (Dex5.0 group) dexmedetomidine in a similar fashion to the control group. Steady-state hemodynamic parameters were recorded. The inferior vena cava was occluded intermittently to assess preload-independent indices. RESULTS: Compared with the control group, changes in the Dex1.0 group were insignificant. In the Dex2.5 group, only the systolic blood pressure was higher (vs control, P = 0.03), and other parameters were insignificant. The Dex5.0 group exhibited a lower heart rate, higher systolic blood pressure, higher arterial elastance (vs control, all P < 0.001), and unaltered cardiac output. The Dex5.0 group showed steeper slopes of end-systolic pressure increment and end-systolic pressure-volume relationship than the control, Dex1.0, and Dex2.5 groups (all P < 0.001). Slopes of end-diastolic pressure decrement and end-diastolic pressure-volume relationship did not differ among groups. CONCLUSION: Dexmedetomidine had no direct myocardial depressant effect in the rat heart in doses that are similar to those encountered under clinical conditions. Dexmedetomidine did not significantly alter the ability of the heart to cope with bradycardia and greatly increased afterload. Their potentially negative impact on cardiac output was effectively attenuated by improved myocardial contractility and preserved diastolic function in healthy subjects.

OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase.

RATIONALE: Increased arginase activity contributes to endothelial dysfunction by competition for l-arginine substrate and reciprocal regulation of nitric oxide synthase (NOS). The rapid increase in arginase activity in human aortic endothelial cells exposed to oxidized low-density lipoprotein (OxLDL) is consistent with post-translational modification or subcellular trafficking. OBJECTIVE: To test the hypotheses that OxLDL triggers reverse translocation of mitochondrial arginase 2 (Arg2) to cytosol and Arg2 activation, and that this process is dependent on mitochondrial processing peptidase, lectin-like OxLDL receptor-1 receptor, and rho kinase. METHODS AND RESULTS: OxLDL-triggered translocation of Arg2 from mitochondria to cytosol in human aortic endothelial cells and in murine aortic intima with a concomitant rise in arginase activity. All of these changes were abolished by inhibition of mitochondrial processing peptidase or by its siRNA-mediated knockdown. Rho kinase inhibition and the absence of the lectin-like OxLDL receptor-1 in knockout mice also ablated translocation. Aminoterminal sequencing of Arg2 revealed 2 candidate mitochondrial targeting sequences, and deletion of either of these confined Arg2 to the cytoplasm. Inhibitors of mitochondrial processing peptidase or lectin-like OxLDL receptor-1 knockout attenuated OxLDL-mediated decrements in endothelial-specific NO production and increases in superoxide generation. Finally, Arg2(-/-) mice bred on an ApoE(-/-) background showed reduced plaque load, reduced reactive oxygen species production, enhanced NO, and improved endothelial function when compared with ApoE(-/-) controls. CONCLUSIONS: These data demonstrate dual distribution of Arg2, a protein with an unambiguous mitochondrial targeting sequence, in mammalian cells, and its reverse translocation to cytoplasm by alterations in the extracellular milieu. This novel molecular mechanism drives OxLDL-mediated arginase activation, endothelial NOS uncoupling, endothelial dysfunction, and atherogenesis.

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.

Arginase Inhibition Reverses Endothelial Dysfunction, Pulmonary Hypertension, and Vascular Stiffness in Transgenic Sickle Cell Mice.

BACKGROUND: In sickle cell disease (SCD), hemolysis results in the release and activation of arginase, an enzyme that reciprocally regulates nitric oxide (NO) synthase activity and thus, NO production. Simply supplementing the common substrate L-arginine, however, fails to improve NO bioavailability. In this study, we tested the hypothesis that arginase inhibition would improve NO bioavailability and thereby attenuate systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD. METHODS: We studied 5-month-old transgenic sickle cell (SC) mice and age matched wild-type (WT) controls. SC mice were treated with the arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH; approximately 400 µg/d) for 4 weeks or left untreated. RESULTS: Vascular arginase activity was significantly higher at baseline in untreated SC mice compared to WT controls (SC versus WT, 346 ± 69.3 vs 69 ± 17.3 pmol urea/mg protein/minute; P = 0.0043; n = 4-5 animals per group). Treatment with ABH may significantly decrease arginase activity to levels near WT controls (SC + ABH 125.2 ± 17.3 pmol urea/mg protein/minute; P = 0.0213). Aortic strips from untreated SC mice showed decreased NO and increased reactive oxygen species (ROS) production (NO: fluorescence rate 0.76 ± 0.14 vs 1.34 ± 0.17 RFU/s; P = 0.0005 and ROS: fluorescence rate 3.96 ± 1.70 vs 1.63 ± 1.20 RFU/s, P = 0.0039; n = 3- animals per group). SC animals treated with ABH for 4 weeks demonstrated NO (fluorescence rate: 1.16 ± 0.16) and ROS (fluorescence rate: 2.02 ± 0.45) levels comparable with age-matched WT controls (n = 3- animals per group). The maximal endothelial-dependent vasorelaxation response to acetylcholine was impaired in aortic rings from SC mice compared with WT (57.7% ± 8.4% vs 80.3% ± 11.0%; P = 0.02; n = 6 animals per group). The endothelial-independent response was not different between groups. In SC mice, the right ventricular cardiac output index and end-systolic elastance were similar (4.60 ± 0.51 vs 2.9 ± 0.85 mL/min/100 g and 0.89 ± 0.48 vs 0.58 ± 0.11 mm Hg/µL), whereas the pulmonary vascular resistance index and right ventricular end-systolic pressure were greater (2.9 ± 0.28 vs 5.5 ± 2.0 mm Hg × min/µL/100 g and 18.9 ± 1.1 vs 23.1 ± 4.0 mm Hg; n = 8 animals per group). Pulse wave velocity (a measure of arterial stiffness) was greater in SC mice compared with WT (3.74 ± 0.54 vs 3.25 ± 0.21 m/s; n = 20 animals per group), arginase inhibition for 4 weeks significantly reduced the vascular SC phenotype to one similar to WT animals (P = 0.0009). CONCLUSIONS: Arginase inhibition improves NO bioavailability and thereby attenuates systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD. Therefore, arginase is a potential therapeutic target in the treatment of cardiovascular dysfunction in SCD.

Effects of dexmedetomidine on oxygenation and lung mechanics in patients with moderate chronic obstructive pulmonary disease undergoing lung cancer surgery: A randomised double-blinded trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor that increases the incidence of postoperative cardiopulmonary morbidity and mortality after lung resection. Dexmedetomidine, a selective α2-adrenoreceptor agonist, has been reported previously to attenuate intrapulmonary shunt during one-lung ventilation (OLV) and to alleviate bronchoconstriction. OBJECTIVE: The objective is to determine whether dexmedetomidine improves oxygenation and lung mechanics in patients with moderate COPD during lung cancer surgery. DESIGN: A randomised, double-blinded, placebo-controlled study. SETTING: Single university hospital. PARTICIPANTS: Fifty patients scheduled for video-assisted thoracoscopic surgery who had moderate COPD. Patients were randomly allocated to a control group or a Dex group (n = 25 each). INTERVENTIONS: In the Dex group, dexmedetomidine was given as an initial loading dose of 1.0  µg  kg(-1) over 10  min followed by a maintenance dose of 0.5  µg  kg(-1)  h(-1) during OLV while the control group was administered a comparable volume of 0.9% saline. Data were measured at 30  min (DEX-30) and 60  min (DEX-60) after dexmedetomidine or saline administration during OLV. MAIN OUTCOME MEASURES: The primary outcome was the effect of dexmedetomidine on oxygenation. The secondary outcome was the effect of dexmedetomidine administration on postoperative pulmonary complications. RESULTS: Patients in the Dex group had a significantly higher PaO2/FIO2 ratio (27.9 ±â€Š5.8 vs. 22.5 ±â€Š8.4 and 28.6 ±â€Š5.9 vs. 21.0 ±â€Š9.9 kPa, P < 0.05), significantly lower dead space ventilation (19.2 ±â€Š8.5 vs. 24.1 ±â€Š8.1 and 19.6 ±â€Š6.7 vs. 25.3 ±â€Š7.8%, P < 0.05) and higher dynamic compliance at DEX-30 and DEX-60 (P = 0.0001 and P = 0.0184) compared with the control group. In the Dex group, the PaO2/FIO2 ratio in the postoperative period was significantly higher (P = 0.022) and the incidence of ICU admission was lower than in the control group. CONCLUSION: Dexmedetomidine administration may provide clinically relevant benefits by improving oxygenation and lung mechanics in patients with moderate COPD undergoing lung cancer surgery. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT 02185430.

Prediction of fluid responsiveness in the beach chair position using dynamic preload indices.

Hemodynamic instability in the beach chair position (BCP) may lead to adverse outcomes. Cardiac preload optimization is a prerequisite to improve hemodynamics. We evaluated the clinical usefulness of dynamic indices for the prediction of fluid responsiveness in BCP patients under general anesthesia. Forty-two patients in the BCP under mechanical ventilation received colloids at 6 ml/kg for 10 min. Stroke volume variation (SVV), pulse pressure variation (PPV), pleth variability index (PVI), and hemodynamic data were measured before and after the fluid challenge. Patients were considered responders to volume expansion if the stroke volume index increased by ≥15 %. The areas under receiver operating characteristic curves for SVV, PPV and PVI were 0.83, 0.81 and 0.74, respectively (p < 0.05), with the corresponding optimal cut-off values of 12, 15 and 10 %. SVV, PPV and PVI can be used to predict fluid responsiveness in the BCP under mechanical ventilation.

Mitochondrial targeting of the Arabidopsis F1-ATPase γ-subunit via multiple compensatory and synergistic presequence motifs.

The majority of mitochondrial proteins are encoded in the nuclear genome and imported into mitochondria posttranslationally from the cytosol. An N-terminal presequence functions as the signal for the import of mitochondrial proteins. However, the functional information in the presequence remains elusive. This study reports the identification of critical sequence motifs from the presequence of Arabidopsis thaliana F1-ATPase γ-subunit (pFAγ). pFAγ was divided into six 10-amino acid segments, designated P1 to P6 from the N to the C terminus, each of which was further divided into two 5-amino acid subdivisions. These P segments and their subdivisions were substituted with Ala residues and fused to green fluorescent protein (GFP). Protoplast targeting experiments using these GFP constructs revealed that pFAγ contains several functional sequence motifs that are dispersed throughout the presequence. The sequence motifs DQEEG (P4a) and VVRNR (P5b) were involved in translocation across the mitochondrial membranes. The sequence motifs IAARP (P2b) and IAAIR (P3a) participated in binding to mitochondria. The sequence motifs RLLPS (P2a) and SISTQ (P5a) assisted in pulling proteins into the matrix, and the sequence motif IAARP (P2b) functioned in Tom20-dependent import. In addition, these sequence motifs exhibit complex relationships, including synergistic functions. Thus, multiple sequence motifs dispersed throughout the presequence are proposed to function cooperatively during protein import into mitochondria.

Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine.

BACKGROUND: Since the urinary concentration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a reliable biomarker of exposure to tobacco smoke, we developed a relatively simple high-throughput chromatographic method to quantify total urinary NNAL concentrations in the general population. METHODS: The high-throughput analytical method was developed using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) to identify and quantify total urinary NNAL concentrations in 10 non-smokers and 15 otherwise healthy smokers. RESULTS: Loss of nitric oxide at m/z 30 was found to be the predominant mass transitioned, and therefore was used as the SIM transition to quantify both NNAL and NNAL-methyl-d3 in urine. The analytical method did not require sample derivatization. Standard curves for total NNAL concentrations were linear between 20 and 1500 pg/mL, with coefficients of determination >0.95. Precision and accuracy ranged from 2.2% to 8.6% (CV) and from -5.6% to 10.9% (percent error), respectively. The lowest limit of quantification was 6.7 pg/mL, and 2.0 pg/mL the lowest limit of detection (LLOD). Total urinary NNAL concentrations in non-smoker subjects were