[Short-term deep sedation strategy in patients with spontaneous intracerebral hemorrhage: a randomized controlled trial].

OBJECTIVE: To evaluate the efficacy and safety of short-term deep sedation strategy in patients with spontaneous intracerebral hemorrhage (ICH) after surgery. METHODS: A perspective, randomized, parallel-group study was conducted. Adult patients with spontaneous ICH and undergoing craniotomy admitted to Daxing Teaching Hospital of Capital Medical University from December 2015 to November 2016 were enrolled. The patients who received surgery were randomly divided into a short-term deep sedation and a slight and middle sedation group. Sufentanil was used as an analgesic drug in all patients and midazolam was used as a sedative after the operation. The patients in the slight and middle sedation group received midazolam 0.05-0.10 mg/kg with a goal of mild sedation [Richmond agitation and sedation scale (RASS) score of -2-1]. The patients in the short-term deep sedation group received midazolam 0.1-0.2 mg/kg with a goal of deep sedation (RASS score of -4 to -3) and a duration of no more than 12 hours. Postoperative sedation, blood pressure changes, laboratory indexes, residual hematoma and clinical outcomes were recorded in two groups. RESULTS: During the study, a total of 183 patients with spontaneous ICH were collected, excluding who was older than 65 years, with shock, and with preoperative Glasgow coma score (GCS) of 3. 106 patients were enrolled in this study, and 53 patients were assigned to the short-term deep sedation group and slight and middle sedation group, respectively. In the slight and middle sedation group, 4 patients received reoperation because of repeated hemorrhage and no patient operated repeatedly in the short-term deep sedation group, and there was a significant difference between the two groups (χ 2 = 4.000, P = 0.045). The number of patients undergoing tracheotomy in the short-term deep sedation group was significantly lower than that in the slight and middle sedation group (9 cases vs. 21 cases, P < 0.05). RASS score within 12 hours after operation of the patients in the short-term deep sedation group was lower than that in slight and middle sedation group [-4 (-4, -2) vs. -2 (-3, -1) at 4 hours, -4 (-4, -2) vs. -1 (-2, 0) at 8 hours, -3 (-4, -2) vs. 0 (-2, 1) at 12 hours, all P < 0.01], sudden restlessness was significantly reduced [times: 1 (0, 1) vs. 3 (2, 3), P < 0.01], and postoperative sedation duration was significantly prolonged [hours: 14.0 (8.3, 20.8) vs. 8.9 (3.4, 15.3), P < 0.05]. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) within 12 hours after operation in the short-term deep sedation group were significantly lower than those of the slight and middle sedation group [SBP (mmHg, 1 mmHg = 0.133 kPa): 136.8±30.5 vs. 149.1±33.5, DBP (mmHg): 85.0 (70.8, 102.3) vs. 89.0 (69.2, 116.7), both P < 0.05]. There were no significant differences in the arterial blood gas, routine blood test or coagulation function between the two groups at 24 hours after operation. The volume of residual hematoma at 2, 7 and 14 days after operation in the short-term deep sedation group was significantly decreased as compared with slight and middle sedation group (mL: 16.4±15.6 vs. 38.2±22.2 at 2 days, 9.6±8.7 vs. 20.6±18.6 at 7 days, 1.2±1.0 vs. 4.4±3.6 at 14 days, all P < 0.05), number of deaths in 3 months were significantly less (5 cases vs. 13 cases), and the patients with favorable prognosis were increased significantly (39 cases vs. 12 cases, both P < 0.05). CONCLUSIONS: The study results showed that short-term deep sedation strategy after surgery can reduce the incidence of adverse events and improve the prognosis of patients with spontaneous ICH, so it is safe and effective.

Adipose tissue-derived stem cells embedded with eNOS restore cardiac function in acute myocardial infarction model.

This study assessed the potential therapeutic efficacy of endothelial NO syntheses (eNOS)-expressing adipose tissue-derived stem cells (ADSCs) on infarcted hearts. We isolated CD29+, CD44+, CD45- cells from adipose tissue. Multipotent property of ADSCs was characterized by induction to differentiate into myogenic, neurogenic, and endothelic lineages. We hypothesized that combination of eNOS over-expression and transplantation of ADSCs could restore NO bioavailability and improve cardiac function in infarcted hearts. Here with several lines of experimental evidences, we demonstrated that ADSCs with eNOS overexpression induced eNOS expression in host endothelial cells and vascular smooth muscle cells, both in vitro and in vivo. This effect was possibly mediated by calcium signal. Transplantation of ADSCs with eNOS embedded showed great therapeutic efficacy in reduction of infarcted size, compared with normal ADSC. Results of this study suggest that ADSCs could be an attractive vehicle for the exogenous eNOS expression into heart after infarction, which is beneficial to restoration of cardiac function. Paracrine effect by mobilizing the host endothelial cells and smooth muscle cells may be the mechanism underlying the therapeutic effect.

S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling.

Hydrogen sulfide (H(2)S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H(2)S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p.), diclofenac (25 and 50 µmol/kg, i.p.), NaHS (50 µmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H(2)S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H(2)S in the pathogenesis of doxorubicin-induced cardiomyopathy.

Synthesis and characterization of quaternized beta-chitin.

Water-soluble 2'-O-hydroxypropyltrimethylammoniumchitin chloride (2'-O-HTACCt) was prepared directly from beta-chitin and 3-chloro-2-hydroxypropyltrimethylammonium chloride (CTA) in basic medium. The effect of alkali concentration, reaction temperature, reaction time, and dosage of CTA on yield and degree of substitution (DS) of 2'-O-HTACCt were studied. These quaternized chitin derivatives were characterized by FTIR and (1)H NMR spectroscopy, conductometric titration, and elemental analysis methods. Research results indicate that beta-chitin can react directly with CTA to produce a water-soluble 2'-O-HTACCt derivative with a high DS. The optimal preparation conditions were determined to be 35-40 wt% (aq NaOH), 40 degrees C (reaction temperature), 6h (reaction time), and 4 (molar ratio of CTA to beta-chitin unit).

Overexpression of CXCR1/CXCR2 on mesenchymal stromal cells may be an effective treatment for acute myocardial infarction.

Bone marrow (BM)-derived mesenchymal stromal cells (MSC) participate in myocardial repair following myocardial infarction (MI). However, their reparative capability is limited, partly because of poor homing abilities. MI is associated with an inflammatory reaction. Interleukin-8 (IL-8) appears to have a fundamental role in regulating neutrophil localization in ischemic tissues through binding CXCR1/CXCR2 receptors, which show major expression on neutrophils. We hypothesize that the application of IL-8 will enhance the recruitment of overexpressing CXCR1/CXCR2 MSC to sites of degenerated tissue of myocardium, decreasing the ischemic region and improving cardiac function.

Role of norepinephrine in development of short-term myocardial hibernation.

AIM: To investigate the role of norepinephrine in the development of short-term myocardial hibernation. METHODS: Hearts were removed from rats and set up as isometrically beating or short-term hibernation models. The hearts were perfused with modified Krebs-Henseleit buffer under a controlled perfusion pressure. The myocardial ultrastructure was examined, and the content of ATP, phosphocreatine, and glycogen in myocardium, the extent of myocyte apoptosis, and the amount of Bcl-2 and Bax products were determined after 120-min ischemia assessed by TUNEL and immunocytochemistry. RESULTS: There was no significant difference between the reserpinized hearts and the NS control group with respect to heart function, myocardial ultrastructure, ATP, phosphocreatine, or glycogen content, myocyte apoptosis, or amount of Bax or Bcl-2 products. However, relative to the normal saline group, in the norepinephrine-treated hearts, heart function, and myocardial ultrastructure deteriorated significantly, apoptosis and amount of Bax product increased significantly, and the ATP, phosphocreatine, and glycogen content decreased significantly, as did the amount of Bcl-2 product. CONCLUSION: Myocardial norepinephrine does not contribute to the development of short-term hibernation, but that exogenous NE can induce progressive decreases in coronary flow and cardiac performance, which might result from the increases in apoptosis and necrosis. Norepinephrine may be an important factor in the deterioration of myocardial structure and function during hibernation, and that anti-adrenergic treatment may be helpful for the development and sustainment of short-term myocardial hibernation.

Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia.

To investigate effects of supplementation of folic acid on the expression of adhesion molecules VCAM-1 in the aortas of rats with hyperhomocysteinemia. Thirty male SD rats (200 +/- 20 g) were invided into 3 groups (n = 10 for each group): control group(Control), high Met group(Met) and Met plus Folate group(Met + Folate), fed. for 45 days. Plasma Hcy levels were higher with the high-methionine diet (140.68 +/- 36.87 micromol/L vs 6.47 +/- 1.10 micromol/L in control rats) an effect which was reduced by folate. Respectively, the aortic expression of adhesion molecules VCAM-1 at protein and mRNA levels were higher in the Met groups than those in the control groups or the Met + Folate groups. A high methionine diet for 45 days was sufficient to induce hyperhomocysteinemia. Folate supplementation prevented elevation of Hcy levels in the blood, and reduced expression of the adhesion molecule VCAM-1. Hyperhomocysteinemia is now regarded as one of the important risk factors for cardiovascular and cerebralvascular disorders.[Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 38(15):1042-50.] Several plausible mechanisms for Hcy-induecd atherosclerosis have been proposed. These include endothelial dysfunction, enhancement of oxidative stress, reduction in NO bioavailability, and augmentation of thrombus formation.[Holven KB, Holm T, Aukrust P, et al. Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects . Am J Med 2001;110(7):536-42; Guba SC, Fonseca V, Fink LM. Hyperhomocysteinemia and thrombosis. Semin Thromb Hemost 1999;25(3):291-309.] However, the precise molecular mechanism is still unclear. Recent reports have suggested a role for inflammatory processes in the pathogenesis of atherosclerosis.[Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2(2):108-15.] Dysfunction of endothelial cells is the key process promoting inflammatory reactions. On injury, endothlial cells are capable of producing various cytokines that participate in inflammatory reactions in the arterial wall. Although results from in vitro studies suggest that Hcy, at pathophysiological concentrations, stimulates chemokine expression in vascular cells, it is unknown whether hyperhomocysteinemia can initiate similar changes, leading to enhanced momocyte adhesion/binding to the vascular endothelium in vivo.[Zeng X, Dai J, Remick DG, Wang X. Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes. Circ Res 2003;93(4):311-20.] On the basis of the potential pathogenic role of chemokines in atherogenesis, the objective of the present study was to investigate that homocsteine may exert its effect in part though adhesion molecules VCAM-1 and that folic acid supplementation may downregulate these inflammatory responses. Male Sprague-Dawley rats (bred from animal centers of Tongji Medical College, Huazhong Science and Technology University) aged 8 weeks were divided into 3 groups(n=10 for each group) and maintained for 45 days on the following diets before the experiments: (1) regular diet; (2) high-metheionine diet, consisting of regular diet plus 1.7% methionine; and (3) high-methionine plus folate -rich diet, consisting of regular diet plus 1.7% methionine and 0.006% folate.[Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res 2000;21(2-3):129-d37.] Plasma and serum samples wee colleced and stored at -80 degrees C after 45 days until analysis. The plasma homocysteine concentration of rats in three groups were determined by high-pressue liquid chromatography. To detect the endothelial expression of adhesion molecules VCAM-1, the thoracic aorta was isolated and dived into segments. These segments were immersion-fixed in 10% neutral-buffered formalin overlight and then embedded in paraffin. Sequential 5 mum paraffin-embedded cross sections were prepared. Immunohistochemical analyisis was performed to detect vascular cell adhesion molecule(VCAM)-1, The fixed cryosections were immediately blcked in 10% horse serum and phosphate baffered saline(PBS) at room temperature for 30 min. Goat polyclonal andibodies against rat VCAM-1(Santa Cruz Biotechnology) were diluted 1:100 in PBS and incubated with the cryosections for 1 h of room temperature. After three washes, the sections were incubated with biotin-conjugated rabbit anti-goat immunoglobulins(Dako) at 1:250 dilution in PBS. After three washes, the samples were mounted in 90% glycerol-PBS. Photographs were taken by use of a light microscope at a mignification of x200.

Antiapoptotic mechanism of insulin in reoxygenation-induced injury in cultured cardiomyocytes of neonatal rats.

To examine the protective effect of insulin on reoxygenation-induced injury and explore the underlying mechanisms, the model of anoxia/reoxygenation (A/R) injury was established by inducing anoxia for 2 h and reoxygenation for 4 h in cultured cardiomyocytes of neonatal rats. The rats were randomized to four groups receiving vehicle, insulin, LY294002, insulin plus LY294002 at the onset of reoxygenation after 2 h of anoxia. At the end of reoxygenation of 4 h, activity of lactate dehydrogenase (LDH) and content of malondialdehyde (MDA) were spectrophotometrically determined, apoptosis of cardiomyocytes were detected by using TUNEL and DNA Ladder, and Western blotting was employed to examine the expression of phosphorylated Akt in all groups. Our results showed that compared with vehicle-treated group, activities of LDH, contents of MDA, apoptosis index (AI) were significantly decreased, and expression of phosphorylated Akt was increased significantly in insulin-treated group. However, changes in LDH, MDA, AI and phosphorylated Akt resulting from insulin were attenuated or abolished by LY294002 (PI3K inhibitor). These data strongly suggest that early administration of insulin at reoxygenation protects cardiomyocytes from reoxygenation-induced apoptosis through PI3K/Akt signaling pathway.