The efficacy of intramuscular ephedrine in preventing hemodynamic perturbations in patients with spinal anesthesia and dexmedetomidine sedation.

Dexmedetomidine is used for sedation during spinal anesthesia. The sympatholytic effect of dexmedetomidine may exacerbate hypotension and bradycardia with spinal anesthesia. This study investigated the effects of prophylactic intramuscular injection of ephedrine in preventing hypotension and bradycardia occurring through combined use of spinal anesthesia and dexmedetomidine. One hundred sixteen patients scheduled for lower extremity orthopedic surgery were randomized into two groups receiving either ephedrine 20 mg intramuscularly or equivalent amount of 0.9% NaCl, both with dexmedetomidine and spinal anesthesia. The primary endpoint was the incidence of hemodynamic perturbations (hypotension or bradycardia event). The secondary endpoint was a rescue doses of ephedrine and atropine. The incidence of hemodynamic perturbations was significantly lower in the ephedrine group compared with to the saline group (26.3% versus 55.9%, p = 0.001). The rescue doses of atropine (0.09 ± 0.21 versus 0.28 ± 0.41, p = 0.001) and ephedrine (1.04 ± 2.89 versus 2.03 ± 3.25, p = 0.007) were also significantly lower in the ephedrine group. There was no differences in number of patients with hypertensive (7.0% versus 11.9%, p = 0.375) or tachycardia (1.8% versus 3.4% p = 0.581) episodes. The use of ephedrine intramuscular injections may be a safe and efficacious option in preventing hemodynamic perturbations in patients who received spinal anesthesia and sedation using dexmedetomidine.

Federated Reinforcement Learning for Training Control Policies on Multiple IoT Devices.

Reinforcement learning has recently been studied in various fields and also used to optimally control IoT devices supporting the expansion of Internet connection beyond the usual standard devices. In this paper, we try to allow multiple reinforcement learning agents to learn optimal control policy on their own IoT devices of the same type but with slightly different dynamics. For such multiple IoT devices, there is no guarantee that an agent who interacts only with one IoT device and learns the optimal control policy will also control another IoT device well. Therefore, we may need to apply independent reinforcement learning to each IoT device individually, which requires a costly or time-consuming effort. To solve this problem, we propose a new federated reinforcement learning architecture where each agent working on its independent IoT device shares their learning experience (i.e., the gradient of loss function) with each other, and transfers a mature policy model parameters into other agents. They accelerate its learning process by using mature parameters. We incorporate the actor-critic proximal policy optimization (Actor-Critic PPO) algorithm into each agent in the proposed collaborative architecture and propose an efficient procedure for the gradient sharing and the model transfer. Using multiple rotary inverted pendulum devices interconnected via a network switch, we demonstrate that the proposed federated reinforcement learning scheme can effectively facilitate the learning process for multiple IoT devices and that the learning speed can be faster if more agents are involved.

Wound Healing Effect of Slightly Acidic Electrolyzed Water on Cutaneous Wounds in Hairless Mice via Immune-Redox Modulation.

Acidic electrolyzed water is an innovative sanitizer having a wide-spectrum of applications in food industry, and healthcare industry but little is known on its effect and mechanism in wound healing. The study was conducted to identify the effect and mechanism of slightly acidic electrolyzed water (SAEW) on cutaneous wounds in hairless mice. SAEW (pH: 5-6.5, oxidation reduction potential: 800 mV, chlorine concentration: 25 ppm) was prepared through electrolysis of water and was applied to the wounds of hairless mice three times a day for seven days. Wound size, immune response and oxidative stress were explored and compared to conventional agents such as Betadine and alcohol. We found that SAEW-treated group showed the highest wound reduction percentage (p<0.01). Antioxidant activities such as glutathione peroxidase, catalase and myeloperoxidase activities of SAEW group surpassed the total reactive oxygen species in skin. Nuclear factor erythroid-2-related-factor-2 and aryl hydrocarbon receptor were upregulated in SAEW group. Further, SAEW recruited the production of intracellular calcium and promoted its utilization for faster healing. In line, SAEW treatment decreased pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, keratinocyte chemoattractant, and tumor necrosis factor-α] in serum. Other hallmarks of wound healing, matrixmetalloproteinases (MMP)1 and MMP9 were also upregulated. Collectively, our study indicates that SAEW is effective in wound healing of hairless mice via immune-redox modulation, and heals better/faster than conventional agents.

Korean red ginseng water extract restores impaired endothelial function by inhibiting arginase activity in aged mice.

Cardiovascular disease is the prime cause of morbidity and mortality and the population ages that may contribute to increase in the occurrence of cardiovascular disease. Arginase upregulation is associated with impaired endothelial function in aged vascular system and thus may contribute to cardiovascular disease. According to recent research, Korean Red Ginseng water extract (KRGE) may reduce cardiovascular disease risk by improving vascular system health. The purpose of this study was to examine mechanisms contributing to age-related vascular endothelial dysfunction and to determine whether KRGE improves these functions in aged mice. Young (10±3 weeks) and aged (55±5 weeks) male mice (C57BL/6J) were orally administered 0, 10, or 20 mg/mouse/day of KRGE for 4 weeks. Animals were sacrificed and the aortas were removed. Endothelial arginase activity, nitric oxide (NO) generation and reactive oxygen species (ROS) production, endothelial nitric oxide synthase (eNOS) coupling, vascular tension, and plasma peroxynitrite production were measured. KRGE attenuated arginase activity, restored nitric oxide (NO) generation, reduced ROS production, and enhanced eNOS coupling in aged mice. KRGE also improved vascular tension in aged vessels, as indicated by increased acetylcholine-induced vasorelaxation and improved phenylephrine-stimulated vasoconstriction. Furthermore, KRGE prevented plasma peroxynitrite formation in aged mice, indicating reduced lipid peroxidation. These results suggest KRGE exerts vasoprotective effects by inhibiting arginase activity and augmenting NO signaling and may be a useful treatment for age-dependent vascular diseases.

Contagious infection-free medical interaction system with machine vision controlled by remote hand gesture during an operation.

Background and objective: Medical image visualization is a requirement in many types of surgery such as orthopaedic, spinal, thoracic procedures or tumour resection to eliminate risk such as "wrong level surgery". However, direct contact with physical devices such as mice or touch screens to control images is a challenge because of the potential risk of infection. To prevent the spread of infection in sterile environments, a contagious infection-free medical interaction system has been developed for manipulating medical images. Methods: We proposed an integrated system with three key modules: hand landmark detection, hand pointing, and hand gesture recognition. A proposed depth enhancement algorithm is combined with a deep learning hand landmark detector to generate hand landmarks. Based on the designed system, a proposed hand-pointing system combined with projection and ray-pointing techniques allows for reducing fatigue during manipulation. A proposed landmark geometry constraint algorithm and deep learning method were applied to detect six gestures including click, open, close, zoom, drag, and rotation. Additionally, a control menu was developed to effectively activate common functions. Results: The proposed hand-pointing system allowed for a large control range of up to 1200 mm in both vertical and horizontal direction. The proposed hand gesture recognition method showed high accuracy of over 97% and real-time response. Conclusion: This paper described the contagious infection-free medical interaction system that enables precise and effective manipulation of medical images within the large control range, while minimizing hand fatigue.

Novel Procedure for Automatic Registration between Cone-Beam Computed Tomography and Intraoral Scan Data Supported with 3D Segmentation.

In contemporary practice, intraoral scans and cone-beam computed tomography (CBCT) are widely adopted techniques for tooth localization and the acquisition of comprehensive three-dimensional models. Despite their utility, each dataset presents inherent merits and limitations, prompting the pursuit of an amalgamated solution for optimization. Thus, this research introduces a novel 3D registration approach aimed at harmonizing these distinct datasets to offer a holistic perspective. In the pre-processing phase, a retrained Mask-RCNN is deployed on both sagittal and panoramic projections to partition upper and lower teeth from the encompassing CBCT raw data. Simultaneously, a chromatic classification model is proposed for segregating gingival tissue from tooth structures in intraoral scan data. Subsequently, the segregated datasets are aligned based on dental crowns, employing the robust RANSAC and ICP algorithms. To assess the proposed methodology's efficacy, the Euclidean distance between corresponding points is statistically evaluated. Additionally, dental experts, including two orthodontists and an experienced general dentist, evaluate the clinical potential by measuring distances between landmarks on tooth surfaces. The computed error in corresponding point distances between intraoral scan data and CBCT data in the automatically registered datasets utilizing the proposed technique is quantified at 0.234 ± 0.019 mm, which is significantly below the 0.3 mm CBCT voxel size. Moreover, the average measurement discrepancy among expert-identified landmarks ranges from 0.368 to 1.079 mm, underscoring the promise of the proposed method.

Incidence of intraoperative hypotension in older patients undergoing total intravenous anesthesia by remimazolam versus propofol: A randomized controlled trial.

BACKGROUND: An increase in the frequency of surgeries among older individuals is observed in some countries. Hypotension is common and exaggerated in older patients and can lead to increased morbidity and mortality. Total intravenous anesthesia is commonly administered with propofol, while remimazolam has been suggested as an alternative to propofol because of advantages such as a more stable hemodynamic profile and less respiratory suppression. We conducted a single-blind, parallel-group randomized controlled trial to compare the incidence of intraoperative hypotension between patients administered with remimazolam and propofol. METHODS: A total of 132 patients, aged between 65 to 80 years and undergoing laparoscopic cholecystectomy or transurethral resection of bladder tumors were randomly assigned to the propofol or remimazolam group with a permuted block system while being blinded to the hypnotic agent. Remifentanil was administered via target-controlled infusion in both groups, with an initial effect-site concentration of 3.0 ng/mL and titration range of 1.5 to 4.0 ng/mL intraoperatively. The primary outcome of this study was the overall incidence of hypotension during general anesthesia. RESULTS: Patients in the propofol group experienced higher intraoperative hypotension than those in the remimazolam group (59.7% vs 33.3%, P = .006). Multivariate logistic regression analysis showed that remimazolam administration was associated with reduced hypotension (adjusted odds ratio, 0.34; 95% CI, 0.16-0.73). Secondary outcomes such as recovery time, delirium, and postoperative nausea and vomiting were comparable in both groups. CONCLUSION: Total intravenous anesthesia with remimazolam was associated with less intraoperative hypotension than propofol in older patients, with a comparable recovery profile.

Modified submental intubation techniques for maxillofacial surgery - A report of five cases.

BACKGROUND: Submental intubation has been the recommended airway management procedure for maxillofacial surgery since proposed by Altemir in 1986. We adopted various submental intubation modifications based on modified intubation protocols and report on the effectiveness and problems of each modified method. CASE: Among a total of 13 submental intubation cases during the last five years, five representative methods are described. The proximal end of the endotracheal tube was protected by a nelaton catheter in case 1, by a suction connector in case 2, and by a dental needle cap in case 3. In case 4, a nasal speculum was used to expand a single route, and in case 5, a laparoscopic trocar was used to secure a single route. CONCLUSIONS: Use of a laparoscopic trocar might be the most effective way to obtain a single submental route. However, considering cost, use of a nasal speculum is also an effective suboptimal solution.

Arginase inhibition by rhaponticin increases L-arginine concentration that contributes to Ca2+-dependent eNOS activation.

Although arginase primarily participates in the last reaction of the urea cycle, we have previously demonstrated that arginase II is an important cytosolic calcium regulator through spermine production in a p32-dependent manner. Here, we demonstrated that rhaponticin (RPT) is a novel medicinal-plant arginase inhibitor and investigated its mechanism of action on Ca2+-dependent endothelial nitric oxide synthase (eNOS) activation. RPT was uncompetitively inhibited for both arginases I and II prepared from mouse liver and kidney. It also inhibited arginase activity in both aorta and human umbilical vein endothelial cells (HUVECs). Using both microscope and FACS analyses, RPT treatments induced increases in cytosolic Ca2+ levels using Fluo-4 AM as a calcium indicator. Increased cytosolic Ca2+ elicited the phosphorylations of both CaMKII and eNOS Ser1177 in a time-dependent manner. RPT incubations also increased intracellular L-arginine (L-Arg) levels and activated the CaMKII/AMPK/Akt/eNOS signaling cascade in HUVECs. Treatment of L-Arg and ABH, arginase inhibitor, increased intracellular Ca2+ concentrations and activated CaMKII-dependent eNOS activation in ECs of WT mice, but, the effects were not observed in ECs of inositol triphosphate receptor type 1 knockout (IP3R1-/-) mice. In the aortic endothelium of WT mice, RPT also augmented nitric oxide (NO) production and attenuated reactive oxygen species (ROS) generation. In a vascular tension assay using RPT-treated aortic tissue, cumulative vasorelaxant responses to acetylcholine (Ach) were enhanced, and phenylephrine (PE)-dependent vasoconstrictive responses were retarded, although sodium nitroprusside and KCl responses were not different. In this study, we present a novel mechanism for RPT, as an arginase inhibitor, to increase cytosolic Ca2+ concentration in a L-Arg-dependent manner and enhance endothelial function through eNOS activation. [BMB Reports 2021; 54(10): 516-521].

Endothelial arginase II: a novel target for the treatment of atherosclerosis.

Oxidized low-density lipoproteins increase arginase activity and reciprocally decrease endothelial NO in human aortic endothelial cells. Here, we demonstrate that vascular endothelial arginase activity is increased in atherogenic-prone apolipoprotein E-null (ApoE(-/-)) and wild-type mice fed a high cholesterol diet. In ApoE(-/-) mice, selective arginase II inhibition or deletion of the arginase II gene (Arg II(-/-) mice) prevents high-cholesterol diet-dependent decreases in vascular NO production, decreases endothelial reactive oxygen species production, restores endothelial function, and prevents oxidized low-density lipoprotein-dependent increases in vascular stiffness. Furthermore, arginase inhibition significantly decreases plaque burden. These data indicate that arginase II plays a critical role in the pathophysiology of cholesterol-mediated endothelial dysfunction and represents a novel target for therapy in atherosclerosis.

Complications of fluid overload during hysteroscopic surgery: cardiomyopathy and epistaxis - A case report.

BACKGROUND: Hysteroscopic surgery has been used in various gynecological fields. However, massive fluid overload can occur as a complication due to persistent infusion of media for uterine cavity distension. We present the case of a woman who developed cardiomyopathy with pulmonary edema and epistaxis during hysteroscopic surgery. CASE: A 76-year-old female underwent hysteroscopic septectomy. She manifested abrupt, active nasal bleeding and regurgitation in the intravenous line. Heart rate, SpO2, and PETCO2 decreased from 55 beats/min to 29 beats/min, from 100% to 56%, and from 31 mmHg to 9 mmHg, respectively. After the operation, brain CT showed bilateral prominent superior ophthalmic vein dilation. Echocardiography showed left ventricle apical ballooning and global hypokinesia. The patient recovered after two days of conservative management, with no sequelae. CONCLUSIONS: Although hysteroscopic surgery is a simple procedure, careful monitoring is necessary to prevent complications from absorption of fluid distending media during the procedure.

Overexpressed p32 localized in the endoplasmic reticulum and mitochondria negatively regulates calcium­dependent endothelial nitric oxide synthase activit.

The p32 protein plays a crucial role in the regulation of cytosolic Ca2+ concentrations ([Ca2+]c) that contributes to the Ca2+­dependent signaling cascade. Using an adenovirus and plasmid p32­overexpression system, the aim of the study was to evaluate the role of p32 in the regulation of [Ca2+] and its potential associated with Ca2+­dependent endothelial nitric oxide synthase (eNOS) activation in endothelial cells. Using electron and confocal microscopic analysis, p32 overexpression was observed to be localized to mitochondria and the endoplasmic reticulum and played an important role in Ca2+ translocation, resulting in increased [Ca2+] in these organelles and reducing cytosolic [Ca2+] ([Ca2+]c). This decreased [Ca2+]c following p32 overexpression attenuated the Ca2+­dependent signaling cascade of calcium/calmodulin dependent protein kinase II (CaMKII)/AKT/eNOS phosphorylation. Moreover, in aortic endothelia of wild­type mice intravenously administered adenovirus encoding the p32 gene, increased p32 levels reduced NO production and accelerated reactive oxygen species (ROS) generation. In a vascular tension assay, p32 overexpression decreased acetylcholine (Ach)­induced vasorelaxation and augmented phenylephrine (PE)­dependent vasoconstriction. Notably, decreased levels of arginase II (ArgII) protein using siArgII were associated with downregulation of overexpressed p32 protein, which contributed to CaMKII­dependent eNOS phosphorylation at Ser1177. These results indicated that increased protein levels of p32 caused endothelial dysfunction through attenuation of the Ca2+­dependent signaling cascade and that ArgII protein participated in the stability of p32. Therefore, p32 may be a novel target for the treatment of vascular diseases associated with endothelial disorders.

Inducible NO synthase dependent S-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction.

Endothelial function is impaired in aging because of a decrease in NO bioavailability. This may be, in part, attributable to increased arginase activity, which reciprocally regulates NO synthase (NOS) by competing for the common substrate, L-arginine. However, the high Km of arginase (>1 mmol/L) compared with NOS (2 to 20 micromol/L) seemingly makes direct competition for substrate unlikely. One of the mechanisms by which NO exerts its effects is by posttranslational modification through S-nitrosylation of protein cysteines. We tested the hypothesis that arginase1 activity is modulated by this mechanism, which serves to alter its substrate affinity, allowing competition with NOS for L-arginine. We demonstrate that arginase1 activity is altered by S-nitrosylation, both in vitro and ex vivo. Furthermore, using site-directed mutagenesis we demonstrate that 2 cysteine residues (C168 and C303) are able to undergo nitrosylation. S-Nitrosylation of C303 stabilizes the arginase1 trimer and reduces its Km value 6-fold. Finally, arginase1 nitrosylation is increased (and thus its Km decreased) in blood vessels from aging rats, likely contributing to impaired NO bioavailability and endothelial dysfunction. This is mediated by inducible NOS, which is expressed in the aging endothelium. These findings suggest that S-nitrosylated arginase1 can compete with NOS for L-arginine and contribute to endothelial dysfunction in the aging cardiovascular system.

Resveratrol is an arginase inhibitor contributing to vascular smooth muscle cell vasoconstriction via increasing cytosolic calcium.

The contractility of vascular smooth muscle cells (VSMCs) controls the lumen diameter of vessels, thus serving a role in regulating blood pressure and organ blood flow. Although arginases are known to have numerous effects in the biological activities of VSMCs, the effects of arginase II on the constriction of VSMCs has not yet been investigated. When conducting a natural products screen for an inhibitor against arginase, the present study identified that a relatively high concentration of resveratrol (RSV) exhibited arginase inhibitory activity. Therefore, the present study investigated whether RSV could regulate VSMCs contractions and the underlying mechanism. Arginase inhibition by RSV led to an increase in the concentration of the substrate L­Arg and an accompanying increase in the cytosol Ca2+ concentration [(Ca2+)c] in VSMCs. The increased [Ca2+]c induced by RSV and L­Arg treatments resulted in CaMKII­dependent MLC20 phosphorylation. The effects of RSV on VSMCs were maintained even when VSMCs were pre­treated with sirtinol, an inhibitor of Sirt proteins. In a vascular tension assay with de­endothelialized aortic vessels, vasoconstrictor responses, which were measured using phenylephrine (PE), were significantly enhanced in the RSV­ and L­Arg­treated vessels. Therefore, although arginase inhibition has exhibited beneficial effects in various diseases, care is required when considering administration of an arginase inhibitor to patients with vessels endothelial dysfunction as RSV can induce vessel contraction.

Arginase II activity regulates cytosolic Ca2+ level in a p32-dependent manner that contributes to Ca2+-dependent vasoconstriction in native low-density lipoprotein-stimulated vascular smooth muscle cells.

Although arginase II (ArgII) is abundant in mitochondria, Ca2+-accumulating organelles, the relationship between ArgII activity and Ca2+ translocation into mitochondria and the regulation of cytosolic Ca2+ signaling are completely unknown. We investigated the effects of ArgII activity on mitochondrial Ca2+ uptake through mitochondrial p32 protein (p32m) and on CaMKII-dependent vascular smooth muscle cell (VSMC) contraction. Native low-density lipoprotein stimulation induced an increase in [Ca2+]m as measured by CoCl2-quenched calcein-AM fluorescence, which was prevented by Arg inhibition in hAoSMCs and reduced in mAoSMCs from ArgII-/- mice. Conversely, [Ca2+]c analyzed with Fluo-4 AM was increased by Arg inhibition and ArgII gene knockout. The increased [Ca2+]c resulted in CaMKII and MLC 20 phosphorylation, which was associated with enhanced vasoconstriction activity to phenylephrine (PE) in the vascular tension assay. Cy5-tagged siRNA against mitochondrial p32 mRNA (sip32m) abolished mitochondrial Ca2+ uptake and induced activation of CaMKII. Spermine, a polyamine, induced mitochondrial Ca2+ uptake and dephosphorylation of CaMKII and was completely inhibited by sip32m incubation. In mAoSMCs from ApoE-null mice fed a high-cholesterol diet (ApoE-/- +HCD), Arg activity was increased, and spermine concentration was higher than that of wild-type mice. Furthermore, [Ca2+]m and p32m levels were elevated, and CaMKII phosphorylation was reduced in mAoSMCs from ApoE-/- +HCD. In vascular tension experiments, an attenuated response to vasoconstrictors in de-endothelialized aorta from ApoE-/- +HCD was recovered by incubation of sip32m. ArgII activity-dependent production of spermine augments Ca2+ transition from the cytosol to the mitochondria in a p32m-dependent manner and regulates CaMKII-dependent constriction in VSMCs.

Arginase Inhibition Suppresses Native Low-Density Lipoprotein-Stimulated Vascular Smooth Muscle Cell Proliferation by NADPH Oxidase Inactivation.

PURPOSE: Vascular smooth muscle cell (VSMC) proliferation induced by native low-density lipoprotein (nLDL) stimulation is dependent on superoxide production from activated NADPH oxidase. The present study aimed to investigate whether the novel arginase inhibitor limonin could suppress nLDL-induced VSMC proliferation and to examine related mechanisms. MATERIALS AND METHODS: Isolated VSMCs from rat aortas were treated with nLDL, and cell proliferation was measured by WST-1 and BrdU assays. NADPH oxidase activation was evaluated by lucigenin-induced chemiluminescence, and phosphorylation of protein kinase C (PKC) ßII and extracellular signal-regulated kinase (ERK) 1/2 was determined by western blot analysis. Mitochondrial reactive oxygen species (ROS) generation was assessed using MitoSOX-red, and intracellular L-arginine concentrations were determined by high-performance liquid chromatography (HPLC) in the presence or absence of limonin. RESULTS: Limonin inhibited arginase I and II activity in the uncompetitive mode, and prevented nLDL-induced VSMC proliferation in a p21Waf1/Cip1-dependent manner without affecting arginase protein levels. Limonin blocked PKCßII phosphorylation, but not ERK1/2 phosphorylation, and translocation of p47phox to the membrane was decreased, as was superoxide production in nLDL-stimulated VSMCs. Moreover, mitochondrial ROS generation was increased by nLDL stimulation and blocked by preincubation with limonin. Mitochondrial ROS production was responsible for the phosphorylation of PKCßII. HPLC analysis showed that arginase inhibition with limonin increases intracellular L-arginine concentrations, but decreases polyamine concentrations. L-Arginine treatment prevented PKCßII phosphorylation without affecting ERK1/2 phosphorylation. CONCLUSION: Increased L-arginine levels following limonin-dependent arginase inhibition prohibited NADPH oxidase activation in a PKCßII-dependent manner, and blocked nLDL-stimulated VSMC proliferation.

Arginase II Contributes to the Ca2+/CaMKII/eNOS Axis by Regulating Ca2+ Concentration Between the Cytosol and Mitochondria in a p32-Dependent Manner.

Background Arginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase ( eNOS ). We tested the hypotheses that arginase II activity participates in the regulation of Ca2+/Ca2+/calmodulin-dependent kinase II / eNOS activation, and this process is dependent on mitochondrial p32. Methods and Results Downregulation of arginase II increased the concentration of cytosolic Ca2+ ([Ca2+]c) and decreased mitochondrial Ca2+ ([Ca2+]m) in microscopic and fluorescence-activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca2+/Ca2+/calmodulin-dependent kinase II . These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca2+ from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II -null mice resulted in reduced p32 protein level. In the aortas of wild-type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO -dependent vasorelaxation. Arginase activity, p32 protein expression, spermine amount, and [Ca2+]m were increased in the aortas from apolipoprotein E (ApoE-/-) mice fed a high-cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca2+/Ca2+/calmodulin-dependent kinase II -dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice. Conclusions These data demonstrate a novel function of arginase II in regulation of Ca2+-dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.

Bupivacaine induced cardiac toxicity mimicking an acute non-ST segment elevation myocardial infarction.

Bupivacaine is widely used as a local anesthetic. Central nervous system (CNS) and cardiovascular toxicity are well known side effects. However, there has been no report of bupivacaine-induced myocardial injury. We present a case of bupivacaine cardiac toxicity mimicking an acute non-ST segment elevation myocardial infarction, which was eventually diagnosed as bupivacaine-induced cardiac toxicity without CNS toxicity. As soon as a healthy young woman at a private clinic was given a spinal anesthesia of 6mg bupivacaine for hemorrhoidectomy, she developed arrhythmia and hypotension. She was transferred to our emergency room. There was an accelerated idioventricular rhythm with ST segment depression on electrocardiogram, coarse breathing sounds with rales on whole lung field and a butterfly sign on the chest radiograph. 2D transthoracic echocardiography (TTE) revealed reduced left ventricle systolic ejection fraction (approximately 27%). There was regional wall motion abnormality of the left ventricle on 2D TTE and the cardiac marker was increased. We diagnosed the patient as having acute non-ST segment elevation myocardial infarction but her impaired cardiac function improved gradually. On the seventh day from admission, there was a complete spontaneous recovery of cardiac function, and coronary angiography revealed a normal coronary artery. Therefore, we firmly believe that bupivacaine directly injures the cardiac cell.

Effects of Combined Rocuronium and Cisatracurium in Laparoscopic Cholecystectomy.

BACKGROUND: Laparoscopic upper abdominal surgery can cause spontaneous respiration due to diaphragmatic stimulation and intra-abdominal CO2 inflation. Therefore, sufficient muscle relaxation is necessary for a safe surgical environment. METHODS: We investigated if the combination of rocuronium and cisatracurium can counteract the delayed onset of cisatracurium's action and delayed recovery of muscle relaxation and whether the dosage of rocuronium, which is metabolized hepatically, can be reduced. A total of 75 patients scheduled for laparoscopic cholecystectomy with an American Society of Anesthesiology physical status I-II, in the age range of 20-60 years, and with a 20-30 kg/m2 body mass index were included in the study. RESULTS: The patients were divided into the following groups: combination group (Group RC, rocuronium 0.3 mg/kg and cisatracurium 0.05 mg/kg), rocuronium group (Group R, rocuronium 0.6 mg/kg), and cisatracurium group (Group C, cisatracurium 0.1 mg/kg), and the onset, 25% duration, recovery index, and addition/time ratio were measured. Patients in Group RC exhibited a significantly different addition/time ratio compared with patients in the other two groups (p = 0.003). CONCLUSION: During laparoscopic cholecystectomy, the 95% effective dose of rocuronium in combination with cisatracurium is expected to provide a sufficient muscle relaxant effect.

Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness.

Endothelial dysfunction and increased arterial stiffness contribute to multiple vascular diseases and are hallmarks of cardiovascular aging. To investigate the effects of aging on shear stress-induced endothelial nitric oxide (NO) signaling and aortic stiffness, we studied young (3-4 mo) and old (22-24 mo) rats in vivo and in vitro. Old rat aorta demonstrated impaired vasorelaxation to acetylcholine and sphingosine 1-phosphate, while responses to sodium nitroprusside were similar to those in young aorta. In a customized flow chamber, aortic sections preincubated with the NO-sensitive dye, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, were subjected to steady-state flow with shear stress increase from 0.4 to 6.4 dyn/cm(2). In young aorta, this shear step amplified 4-amino-5-methylamino-2',7'-difluorofluorescein fluorescence rate by 70.6 +/- 13.9%, while the old aorta response was significantly attenuated (23.6 +/- 11.3%, P < 0.05). Endothelial NO synthase (eNOS) inhibition, by N(G)-monomethyl-l-arginine, abolished any fluorescence rate increase. Furthermore, impaired NO production was associated with a significant reduction of the phosphorylated-Akt-to-total-Akt ratio in aged aorta (P < 0.05). Correspondingly, the phosphorylated-to-total-eNOS ratio in aged aortic endothelium was markedly lower than in young endothelium (P < 0.001). Lastly, pulse wave velocity, an in vivo measure of vascular stiffness, in old rats (5.99 +/- 0.191 m/s) and in N(omega)-nitro-l-arginine methyl ester-treated rats (4.96 +/- 0.118 m/s) was significantly greater than that in young rats (3.64 +/- 0.068 m/s, P < 0.001). Similarly, eNOS-knockout mice demonstrated higher pulse wave velocity than wild-type mice (P < 0.001). Thus impaired Akt-dependent NO synthase activation is a potential mechanism for decreased NO bioavailability and endothelial dysfunction, which likely contributes to age-associated vascular stiffness.