Workplace violence in the emergency department: a systematic review and meta-analysis.

OBJECTIVES: Emergency departments (EDs) currently face a widely acknowledged issue of workplace violence (WPV) against healthcare workers (HCWs). WPV in the ED occurs in different forms and from different types of instigators; its prevalence also varies in different regions of the world. This study investigates the incidence of WPV among ED staff and identifies the types of instigators involved. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Using PubMed and SCOPUS databases, a search for WPV against ED physicians and nurses was conducted, yielding 301 articles. Studies were excluded if measuring violence between HCWs or against prehospital personnel. Studies assessing WPV not in the ED, such as domestic violence that occurred before arrival to the ED, and studies investigating violence involving alcohol/drug use or individuals with a psychiatric diagnosis were also excluded. This study used a random-effects meta-analysis to examine the prevalence of WPV in the ED, including types of violence, instigators, and professions of the victims. RESULTS: In total, 26 articles were selected for this study. There were 9072 cases of WPV in the ED; 6575 (72%) cases involved verbal violence and 1639 (18%) related to physical abuse. Among the ED workers involved, 2112 (36.5%) were physicians, 3225 (55.7%) were nurses and 455 (7.8%) other ED staff. There were 2578 instigators, of whom 1340 (52%) were family members, 700 (27%) were patients and 538 (21%) were other relatives/friends. The overall prevalence of verbal violence was 0.77 (95% confidence interval [CI]: 0.72-0.82, I2 = 87%), suggesting 77% of ED staff reported exposure to WPV. The prevalence of violence from patients as instigators was 0.24 (95% CI: 0.18-31, I2 = 93%). CONCLUSIONS: WPV in the ED is a serious issue as most nurses and physicians are significantly exposed to verbal and/or physical abuse. Further studies should focus on factors influencing the different types of WPV, which ED professions are most at risk and interventions to prevent WPV in the ED.

Calcium signalling in the endothelium.

Elevations in cytosolic Ca2+ concentration are the usual initial response of endothelial cells to hormonal and chemical transmitters and to changes in physical parameters, and many endothelial functions are dependent upon changes in Ca2+ signals produced. Endothelial cell Ca2+ signalling shares similar features with other electrically non-excitable cell types, but has features unique to endothelial cells. This chapter discusses the major components of endothelial cell Ca2+ signalling.

Insulin inhibits coronary endothelial cell calcium entry and coronary artery relaxation.

Hyperinsulinemia is closely related to coronary artery disease. Endothelial cells are important for the control of vascular tone, and dysfunction of endothelial cells has been implicated in coronary artery disease. The direct effects of insulin on coronary endothelial cells are nonetheless unknown. In this study, the acute effects of high-dose insulin were investigated on agonist-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) in porcine coronary endothelial cells and coronary relaxation. Bradykinin (10 n M ) and cyclopiazonic acid (100 microM), an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, provoked large increases in [Ca(2+)](i) in coronary endothelial cells. This increase was dose-dependently inhibited by a 10-min preincubation with high doses of insulin (10, 30, 100 mU/ml). Under Ca(2+)-free conditions, bradykinin and cyclopiazonic acid provoked transient, small increases in [Ca(2+)](i). These increases were not affected by pretreatment with insulin (100 mU/ml). Bradykinin (1, 10, 100, 1,000 n M ) and cyclopiazonic acid (10 microM) significantly relaxed porcine coronary artery rings precontracted with histamine (1 microM). The vasodilator effects of bradykinin and cyclopiazonic acid were dose-dependently inhibited by insulin. These acute effects were not observed at physiologic concentrations. Our data indicate that high-dose insulin inhibits agonist-induced Ca(2+) response in coronary endothelial cells and attenuates agonist-induced coronary vasodilatation. The study suggests that hyperinsulinemia might be associated with coronary artery disease via derangement of endothelial Ca(2+)-dependent functions.

New spirostanol steroids and steroidal saponins from roots and rhizomes of Dracaena angustifolia and their antiproliferative activity.

The MeOH extract of Nam ginseng (roots and rhizomes of Dracaena angustifolia) afforded nine new compounds, including three spirostanol sapogenins, named namogenins A-C (1-3), four spirostanol saponins, named namonins A-D (4-7), a furostanol saponin, named namonin E (8), and a pregnan glycoside, named namonin F (9), along with another eight known steroidal saponins (10-17). Their structures were determined on the basis of spectral analyses and chemical methods. All compounds were tested for their antiproliferative activity against murine colon 26-L5 carcinoma, human HT-1080 fibrosarcoma, and B-16 BL6 melanoma cells. Compounds 4, 5, and 10 showed potent antiproliferative activity against HT-1080 fibrosarcoma cells, having IC(50) values of 0.2, 0.3, and 0.6 microM, respectively, comparable to that of doxorubicin.

Triterpene saponins from Vietnamese ginseng (Panax vietnamensis) and their hepatocytoprotective activity.

The methanol extract of Vietnamese ginseng (Panax vietnamensis) was found to possess hepatocytoprotective effects on D-galactosamine (D-GalN)/tumor necrosis factor-alpha (TNF-alpha)-induced cell death in primary cultured mouse hepatocytes. Further chemical investigation of the extract afforded two new dammarane-type triterpene saponins, ginsenoside Rh(5) (1) and vina-ginsenoside R(25) (2), as well as eight known dammarane-type triterpene saponins, majonoside R(2) (3), pseudo-ginsenoside RT(4) (4), vina-ginsenosides R(1) (5), R(2) (6), and R(10) (7), ginsenosides Rg(1) (8), Rh(1) (9), and Rh(4) (10), and a known sapogenin protopanaxatriol oxide II (11). Their structures were elucidated on the basis of spectral analysis. In addition, by the using LC-electrospray ionization (ESI)-MS method, five known saponins, ginsenosides Rb(1), Rb(2), Rc, Rd, and Re (12--16), were also identified in the extract. Among the compounds isolated, majonoside R(2) (3), the main saponin in Vietnamese ginseng, showed strong protective activity against D-GalN/TNF-alpha-induced cell death in primary cultured mouse hepatocytes. This demonstrates that the hepatocytoprotective effect of Vietnamese ginseng is due to dammarane-type triterpene saponins that have an ocotillol-type side chain, a characteristic constituent of Vietnamese ginseng.

Myosin light chain kinase regulates capacitative ca(2+) entry in human monocytes/macrophages.

Monocytes/macrophages are present in all stages of atherosclerosis. Although many of their activities depend to various extents on changes in intracellular Ca(2+) concentration ([Ca(2+)](i)), mechanisms regulating [Ca(2+)](i) in these cells remain unclear. We aimed to explore the role of myosin light chain kinase (MLCK) in Ca(2+) signaling in freshly isolated human monocytes/macrophages. Large capacitative Ca(2+) entry (CCE) was observed under fura 2 fluoroscopy in human monocytes/macrophages treated with thapsigargin and cyclopiazonic acid. ML-9 and wortmannin, 2 structurally different inhibitors of MLCK, dose-dependently (1 to 100 micromol/L) prevented CCE and completely did so at 100 micromol/L, whereas inhibitors of tyrosine kinase and protein kinase C had only partial effects. Western blotting showed that thapsigargin significantly caused myosin light chain phosphorylation, which was almost completely blocked by ML-9 (100 micromol/L) and wortmannin (100 micromol/L). ML-9 also dose-dependently (1 to 100 micromol/L) inhibited this phosphorylation, which was well correlated with its inhibition of CCE. Transfection with MLCK antisense completely prevented CCE in response to thapsigargin and cyclopiazonic acid, whereas MLCK sense had no effect. These data strongly indicate that MLCK regulates CCE in human monocytes/macrophages. The study suggests a possible involvement of MLCK in many Ca(2+)-dependent activities of monocytes/macrophages.

Myosin light-chain kinase regulates endothelial calcium entry and endothelium-dependent vasodilation.

Activation of smooth muscle myosin light-chain kinase (MLCK) causes contraction. Here we have proven that MLCK controls Ca2+ entry (CE) in endothelial cells (ECs): MLCK antisense oligonucleotides strongly prevented bradykinin (BK)- and thapsigargin (TG)-induced endothelial Ca2+ response, while MLCK sense did not. We also show that the relevant mechanism is not phosphorylation of myosin light-chain (MLC): MLC phosphorylation by BK required CE, but MLC phosphorylation caused by the phosphatase inhibitor calyculin A did not trigger Ca2+ response. Most important, we provide for the first time strong evidence that, in contrast to its role in smooth muscle cells, activation of MLCK in ECs stimulates the production of important endothelium-derived vascular relaxing factors: MLCK antisense and MLCK inhibitors abolished BK- and TG-induced nitric oxide production, and MLCK inhibitors substantially inhibited acetylcholine-stimulated hyperpolarization of smooth muscle cell membrane in rat mesenteric artery. These results indicate that MLCK controls endothelial CE, but not through MLC phosphorylation, and unveils a hitherto unknown physiological function of the enzyme: vasodilation through its action in endothelial cells. The study discovers a counter-balancing role of MLCK in the regulation of vascular tone.

Calcium signalling in endothelial cells.

Vascular endothelial cells are ubiquitous for their presence in each and every vessel and unique for their multifunctional nature. A large number of endothelial functions depend to various extents on changes in intracellular Ca(2+) concentration. Reviewed are endothelial Ca(2+) stores, Ca(2+) channels, and in-out-in Ca(2+) signalling events, from ligand-binding on the plasma membrane into depletion of intracellular Ca(2+) stores and therefrom out to transplasmalemmal Ca(2+) entry that is of prime importance for many endothelial functions. Special emphasis is placed on mechanisms regulating store-operated Ca(2+) entry including a Ca(2+) influx factor, the vesicle secretion-like model, the conformational coupling model, the membrane potential, cytochrome P450, protein tyrosine kinase, myosin light chain kinase and nitric oxide.

Midkine inhibits bradykinin-stimulated Ca(2+) signaling and nitric oxide production in endothelial cells.

Effects of the heparin-binding growth factor midkine (MK) were investigated on endothelial Ca(2+) signaling and nitric oxide (NO) production. Bradykinin (10 nM) and thapsigargin (1 microM) provoked large Ca(2+) influxes under fura-2/AM fluoroscopy. Pretreatment with human MK dose-dependently (1-500 ng/ml) inhibited the Ca(2+) response to bradykinin but not that to thapsigargin. Anti-MK antibody prevented this effect. In Ca(2+)-free medium, MK greatly inhibited intracellular Ca(2+) store release by bradykinin and not that by thapsigargin, which effect was prevented by the antibody. Bradykinin increased NO production by 6.7-fold, which was inhibited 6, 44, 79, and 90% by MK at 1, 10, 100, and 500 ng/ml, respectively. MK did not affect thapsigargin-induced NO production. Our data clearly indicate that MK inhibits bradykinin-induced Ca(2+) response and NO production from endothelial cells.

Increased cytosolic Ca(2+) concentration in endothelial cells by calmodulin antagonists.

Many functions of endothelial cells are Ca(2+)/calmodulin dependent, whereas the role of calmodulin in the regulation of cytosolic Ca(2+) ([Ca(2+)](i)) remains largely unexplained. In the present study, effects of various calmodulin antagonists on [Ca(2+)](i) were investigated in cultured aortic endothelial cells loaded with the Ca(2+)-sensitive dye fura-2/AM, and were compared with those of calmodulin-dependent protein kinase II (CaM kinase II) inhibitors. The calmodulin antagonists W-7, calmidazolium and fendiline provoked dose-dependent increases in [Ca(2+)](i). However, the CaM kinase II inhibitors KN-93 and lavendustin C had no effect on [Ca(2+)](i). In the absence of extracellular Ca(2+), pretreatment of cells with bradykinin (BK) and thapsigargin completely prevented W-7-stimulated increase in [Ca(2+)](i). Alternatively, pretreatment with W-7 also completely blocked BK- and thapsigargin-stimulated increases in [Ca(2+)](i). The time course of the Ca(2+)-response in W-7 treated cells was identical to that in thapsigargin-treated cells, but not that in BK-stimulated cells, suggesting that calmodulin antagonists could share a common signaling pathway with thapsigargin to increase [Ca(2+)](i) in endothelial cells. These findings indicate that calmodulin is involved in the regulation of [Ca(2+)](i), and may play an important role in the uptake of Ca(2+) to intracellular stores.

Involvement of myosin light-chain kinase in chloride-sensitive Ca2+ influx in porcine aortic endothelial cells.

OBJECTIVES: This study was designed to investigate the involvement of myosin light-chain kinase (MLCK) in bradykinin- and thapsigargin-induced changes in intracellular Cl- and Ca2+ concentrations ([Cl-]i; [Ca2+]i) in porcine aortic endothelial cells. METHODS: Using the fluorescent probes N-ethoxycarbonylmethyl-6-methoxyquinolinium bromide (MQAE) and fura-2/AM, the effects of different MLCK inhibitors on bradykinin- and thapsigargin-induced changes in [Cl-]i and [Ca2+]i were assessed. RESULTS: Bradykinin and thapsigargin significantly decreased the MQAE fluorescence intensity, which indicates increased [Cl-]i; these changes were reversed by removal of extracellular chloride (Cl-o) and were significantly inhibited by Cl(-)-channel inhibitor N-phenylanthranilic acid but not by Na(+)-K(+)-Cl- cotransport inhibitor furosemide. Pretreatment with ML-9 and wortmannin, two different selective inhibitors of MLCK, significantly reduced these changes in a dose-dependent manner. The inhibitory effects of ML-9 and wortmannin on the Cl- responses were not significantly different and were not additive. Bradykinin and thapsigargin provoked large increases in [Ca2+]i, which were significantly diminished by removal of Cl-o and by pretreatment with the Cl(-)-channel inhibitor N-phenylanthranilic acid. CONCLUSIONS: The study shows that an increase in [Cl-]i may be involved in the Ca2+ influx in response to bradykinin and thapsigargin and that MLCK might be involved in the Cl- response. We suggest that MLCK might be involved in the Cl(-)-sensitive endothelial Ca2+ responses to bradykinin and thapsigargin.