Antipsychotic Drugs Inhibit Platelet Aggregation via P2Y 1 and P2Y 12 Receptors.

Antipsychotic drugs (APDs) used to treat clinical psychotic syndromes cause a variety of blood dyscrasias. APDs suppress the aggregation of platelets; however, the underlying mechanism remains unknown. We first analyzed platelet aggregation and clot formation in platelets treated with APDs, risperidone, clozapine, or haloperidol, using an aggregometer and rotational thromboelastometry (ROTEM). Our data indicated that platelet aggregation was inhibited, that clot formation time was increased, and that clot firmness was decreased in platelets pretreated with APDs. We also examined the role two major adenosine diphosphate (ADP) receptors, P2Y1 and P2Y12, play in ADP-mediated platelet activation and APD-mediated suppression of platelet aggregation. Our results show that P2Y1 receptor stimulation with ADP-induced calcium influx was inhibited by APDs in human and rats' platelets, as assessed by in vitro or ex vivo approach, respectively. In contrast, APDs, risperidone and clozapine, alleviated P2Y12-mediated cAMP suppression, and the release of thromboxane A2 and arachidonic acid by activated platelets decreased after APD treatment in human and rats' platelets. Our data demonstrate that each APD tested significantly suppressed platelet aggregation via different mechanisms.

NRIP is newly identified as a Z-disc protein, activating calmodulin signaling for skeletal muscle contraction and regeneration.

Nuclear receptor interaction protein (NRIP, also known as DCAF6 and IQWD1) is a Ca(2+)-dependent calmodulin-binding protein. In this study, we newly identify NRIP as a Z-disc protein in skeletal muscle. NRIP-knockout mice were generated and found to have reduced muscle strength, susceptibility to fatigue and impaired adaptive exercise performance. The mechanisms of NRIP-regulated muscle contraction depend on NRIP being downstream of Ca(2+) signaling, where it stimulates activation of both 'calcineurin-nuclear factor of activated T-cells, cytoplasmic 1' (CaN-NFATc1; also known as NFATC1) and calmodulin-dependent protein kinase II (CaMKII) through interaction with calmodulin (CaM), resulting in the induction of mitochondrial activity and the expression of genes encoding the slow class of myosin, and in the regulation of Ca(2+) homeostasis through the internal Ca(2+) stores of the sarcoplasmic reticulum. Moreover, NRIP-knockout mice have a delayed regenerative capacity. The amount of NRIP can be enhanced after muscle injury and is responsible for muscle regeneration, which is associated with the increased expression of myogenin, desmin and embryonic myosin heavy chain during myogenesis, as well as for myotube formation. In conclusion, NRIP is a novel Z-disc protein that is important for skeletal muscle strength and regenerative capacity.

Sedation for gastrointestinal endoscopy with the application of target-controlled infusion.

BACKGROUND/AIMS: A majority of esophagogastroduodenoscopy (EGD) and colonoscopy procedures are performed under sedation, with the intravenous administration of a hypnotic agent combined with an opioid analgesic agent. The goal of our study was to establish the quality and plausibility of target-controlled infusion (TCI) as a sedation mechanism for upper and lower gastrointestinal (GI) endoscopies. MATERIALS AND METHODS: A randomized, single-blinded, controlled clinical trial was arranged in a local community hospital. In total, 100 adult outpatients scheduled for upper and lower GI endoscopies were included and randomly allocated to a control group (n=50) and a TCI group (n=50). The sedation quality was assessed using the simplified quality of an anesthesia scoring system. Categorical parameters were compared using Pearson's chi-square test. Continuous parameters that were normally distributed were further compared using Student's t-test, and the others were compared using the Mann-Whitney test. RESULTS: The significantly lower anesthesia quality score in the TCI group (12.2 vs. 12.7) indicated that the anesthesia quality was better in this group. CONCLUSION: This study showed that sedation using TCI for GI endoscopy provided safe and effective sedation and was associated with a better sedation quality. We believe that TCI can be used to provide routine sedation for patients receiving GI endoscopy.

Regulation of neutrophil phagocytosis of Escherichia coli by antipsychotic drugs.

Antipsychotic drugs (APDs) have been used to ease the symptoms of schizophrenia. APDs have recently been reported to regulate the immune response. Our previous studies revealed that the atypical APDs risperidone and clozapine and the typical APD haloperidol can inhibit the phagocytic ability of macrophages. Our research next determined the effects of APDs on the phagocytic ability of neutrophils, which are the most abundant type of white blood cells in mammals. Here we provide evidence that clozapine and haloperidol can induce increased phagocytic uptake of Escherichia coli by differentiated HL-60 cells and by purified human neutrophils. Furthermore, clozapine and haloperidol can increase the myeloperoxidase activity and IL-8 production in neutrophils. Our results also show that clozapine can inhibit E. coli survival within differentiated HL-60 cells. Furthermore, clozapine and haloperidol are shown to enhance cell surface Mac-1 expression and the activated AKT signaling pathway in purified neutrophils exposed to E. coli. These results indicate that clozapine and haloperidol can increase the phagocytic ability of neutrophils by increasing AKT activation when cells are exposed to bacteria.

The caffeic acid in aqueous extract of Tournefortia sarmentosa enhances neutrophil phagocytosis of Escherichia coli.

Tournefortia sarmentosa, a Chinese herbal medicine, is considered an antioxidant or a detoxicating agent. Recently T. sarmentosa has received attention for its effects on the immune response. Here we provide evidence that aqueous extract of T. sarmentosa can induce increased phagocytic uptake of Escherichia coli by differentiated HL-60 cells and by neutrophils. Our results also revealed that T. sarmentosa can inhibit E. coli survival within differentiated HL-60 cells. Furthermore, aqueous extract of T. sarmentosa has been shown to enhance cell surface Mac-1 expression and the activated AKT signaling pathway in E. coli-stimulated neutrophils. We also examined the effect of each constituents in aqueous extract of T. sarmentosa on phagocytic uptake of E. coli by differentiated HL-60 cells or neutrophils. Bacterial survival, cell surface Mac-1 expression, and AKT activation of neutrophils were also examined. Our results showed that caffeic acid is an important constituent in mediating aqueous extract of T. sarmentosa-induced phagocytic uptake. Taken together, these results suggest that aqueous extract of T. sarmentosa exerts effects that enhance inflammatory responses by improving phagocytic capability, inhibiting bacterial survival within cells, and increasing Mac-1 expression of neutrophils.

Phospholipase A/Acyltransferase enzyme activity of H-rev107 inhibits the H-RAS signaling pathway.

BACKGROUND: H-rev107, also called HRASLS3 or PLA2G16, is a member of the HREV107 type II tumor suppressor gene family. Previous studies showed that H-rev107 exhibits phospholipase A/acyltransferase (PLA/AT) activity and downregulates H-RAS expression. However, the mode of action and the site of inhibition of H-RAS by H-rev107 are still unknown. RESULTS: Our results indicate that H-rev107 was co-precipitated with H-RAS and downregulated the levels of activated RAS (RAS-GTP) and ELK1-mediated transactivation in epidermal growth factor-stimulated and H-RAS-cotransfected HtTA cervical cancer cells. Furthermore, an acyl-biotin exchange assay demonstrated that H-rev107 reduced H-RAS palmitoylation. H-rev107 has been shown to be a PLA/AT that is involved in phospholipid metabolism. Treating cells with the PLA/AT inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) or methyl arachidonyl fluorophosphate (MAFP) alleviated H-rev107-induced downregulation of the levels of acylated H-RAS. AACOCF3 and MAFP also increased activated RAS and ELK1-mediated transactivation in H-rev107-expressing HtTA cells following their treatment with epidermal growth factor. In contrast, treating cells with the acyl-protein thioesterase inhibitor palmostatin B enhanced H-rev107-mediated downregulation of acylated H-RAS in H-rev107-expressing cells. Palmostatin B had no effect on H-rev107-induced suppression of RAS-GTP levels or ELK1-mediated transactivation. These results suggest that H-rev107 decreases H-RAS activity through its PLA/AT activity to modulate H-RAS acylation. CONCLUSIONS: We made the novel observation that H-rev107 decrease in the steady state levels of H-RAS palmitoylation through the phospholipase A/acyltransferase activity. H-rev107 is likely to suppress activation of the RAS signaling pathway by reducing the levels of palmitoylated H-RAS, which decreases the levels of GTP-bound H-RAS and also the activation of downstream molecules. Our study further suggests that the PLA/AT activity of H-rev107 may play an important role in H-rev107-mediated RAS suppression.

Effect of aqueous extract of Tournefortia sarmentosa on the regulation of macrophage immune response.

Tournefortia sarmentosa, a Chinese herbal medicine, is considered an antioxidant or a detoxicant agent. Recent studies have shown that T. sarmentosa plays an important role in inhibiting low-density-lipoprotein oxidation and attenuating acetaminophen-induced hepatotoxicity. However, information regarding the signaling mechanism of T. sarmentosa-mediated immunoregulation is still limited. Here, we provide evidence that treating macrophages with T. sarmentosa extract leads to a decrease in reactive oxygen species (ROS) production and subsequently suppresses phosphorylated ERK1/2. In contrast, our data revealed that T. sarmentosa extract increases macrophage phagocytosis and adhesion. Also, T. sarmentosa extract activates phosphorylated p38 MAPK in macrophages. We further discovered that T. sarmentosa extract could increase the lipopolysaccharides-stimulated IL-6, IL-8, and TNF-α production of macrophages. This result suggests that T. sarmentosa extract might enhance inflammation. Taken together, our results suggest that T. sarmentosa extract exerts dual functions on the macrophages: suppressing ROS within cells and enhancing inflammatory responses by improving phagocytic ability and proflammatory cytokine release.

Regulation of macrophage immune responses by antipsychotic drugs.

Antipsychotic drugs (APDs) have been used to ease clinical psychotic symptoms. APDs have also been recently discovered to induce immune regulation. Our previous studies found that atypical APDs risperidone and clozapine could inhibit INF-γ production of human peripheral blood mononuclear cells (PBMC) and could inhibit Th1 differentiation. This study further investigates APD effects on monocyte-derived macrophages, which are the major antigen-presenting cells in PBMC. Our data suggest that adhesion, phagocytosis and reactive oxygen species production of monocytic cell lines would be inhibited by haloperidol, risperidone or clozapine. Also, that APDs inhibited the production of LPS-stimulated macrophages IL-6 and IL-8 suggests that risperidone and clozapine may inhibit inflammation. We further discovered that risperidone and clozapine could inhibit IL-12 production and increase IL-10 production of LPS-stimulated macrophages. These results indicated that risperidone and clozapine could inhibit Th1 differentiation not only by increasing INF-γ production of PBMC but by inhibiting the release of Th1-inducing cytokines and increasing Th2-inducing cytokines of LPS-stimulated macrophages to modulate and regulate immune responses.

H-rev107 regulates prostaglandin D2 synthase-mediated suppression of cellular invasion in testicular cancer cells.

BACKGROUND: H-rev107 is a member of the HREV107 type II tumor suppressor gene family which includes H-REV107, RIG1, and HRASLS. H-REV107 has been shown to express at high levels in differentiated tissues of post-meiotic testicular germ cells. Prostaglandin D2 (PGD2) is conjectured to induce SRY-related high-mobility group box 9 (SOX9) expression and subsequent Sertoli cell differentiation. To date, the function of H-rev107 in differentiated testicular cells has not been well defined. RESULTS: In the study, we found that H-rev107 was co-localized with prostaglandin D2 synthase (PTGDS) and enhanced the activity of PTGDS, resulting in increase of PGD2 production in testis cells. Furthermore, when H-rev107 was expressed in human NT2/D1 testicular cancer cells, cell migration and invasion were inhibited. Also, silencing of PTGDS would reduce H-rev107-mediated increase in PGD2, cAMP, and SOX9. Silencing of PTGDS or SOX9 also alleviated H-rev107-mediated suppression of cell migration and invasion. CONCLUSIONS: These results revealed that H-rev107, through PTGDS, suppressed cell migration and invasion. Our data suggest that the PGD2-cAMP-SOX9 signal pathway might play an important role in H-rev107-mediated cancer cell invasion in testes.

Involvement of the prostaglandin D2 signal pathway in retinoid-inducible gene 1 (RIG1)-mediated suppression of cell invasion in testis cancer cells.

Retinoid-inducible gene 1 (RIG1), also called tazarotene-induced gene 3, belongs to the HREV107 gene family, which contains five members in humans. RIG1 is expressed in high levels in well-differentiated tissues, but its expression is decreased in cancer tissues and cancer cell lines. We found RIG1 to be highly expressed in testicular cells. When RIG1 was expressed in NT2/D1 testicular cancer cells, neither cell death nor cell viability was affected. However, RIG1 significantly inhibited cell migration and invasion in NT2/D1 cells. We found that prostaglandin D2 synthase (PTGDS) interacted with RIG1 using yeast two-hybrid screens. Further, we found PTGDS to be co-localized with RIG1 in NT2/D1 testis cells. In RIG1-expressing cells, elevated levels of prostaglandin D2 (PGD2), cAMP, and SRY-related high-mobility group box 9 (SOX9) were observed. This indicated that RIG1 can enhance PTGDS activity. Silencing of PTGDS expression significantly decreased RIG1-mediated cAMP and PGD2 production. Furthermore, silencing of PTGDS or SOX9 alleviated RIG1-mediated suppression of migration and invasion. These results suggest that RIG1 will suppress cell migration/invasion through the PGD2 signaling pathway. In conclusion, RIG1 can interact with PTGDS to enhance its function and to further suppress NT2/D1 cell migration and invasion. Our study suggests that RIG1-PGD2 signaling might play an important role in cancer cell suppression in the testis.

Clozapine inhibits Th1 cell differentiation and causes the suppression of IFN-γ production in peripheral blood mononuclear cells.

Antipsychotic drugs (APDs) are widely used to alleviate a number of psychic disorders and may have immunomodulatory effects. However, the previous studies of cytokine and immune regulation in APDs are quite inconsistent. The aim of this study was to examine the in vitro effects of different ADPs on cytokine production by peripheral blood mononuclear cells (PBMCs). We examined the effects of risperidone, clozapine, and haloperidol on the production of phorbol myristate acetate and ionomycin-induced interferon-γ (IFN-γ)/interleukin (IL)-4 in PBMCs by using intracellular staining. Real-time quantitative PCR and Western blot were used to further examine the expression changes of some critical transcription factors related to T-cell differentiation in antipsychotic-treated PBMCs. Our results indicated that clozapine can suppress the stimulated production of IFN-γ by 30.62%, whereas haloperidol weakly enhances the expression of IFN-γ. Differences in IL-4 production or in the number of CD4+ T cells were not observed in cells treated with different APDs. Furthermore, clozapine and risperidone inhibited the T-bet mRNA and protein expression, which are critical to Th1 differentiation. Also, clozapine can enhance the expression of Signal Transducer and Activator of Transcription 6 and GATA3, which are critical for the differentiation of Th2 cells. The results suggested that clozapine and haloperidol may induce different immunomodulatory effects on the immune system.

NRIP enhances HPV gene expression via interaction with either GR or E2.

We previously identified a gene, nuclear receptor-interaction protein (NRIP), which functions as a transcription cofactor in glucocorticoid receptor (GR) and human papillomavirus E2 (HPV E2)-driven gene expression. Here, we comprehensively evaluated the role of NRIP in HPV-16 gene expression. NRIP acts as a transcription cofactor to enhance GR-regulated HPV-16 gene expression in the presence of hormone. NRIP also can form complex with E2 that caused NRIP-induced HPV gene expression via E2-binding sites in a hormone-independent manner. Furthermore, NRIP can associate with GR and E2 to form tri-protein complex to activate HPV gene expression via GRE, not the E2-binding site, in a hormone-dependent manner. These results indicate that NRIP and GR are viral E2-binding proteins and that NRIP regulates HPV gene expression via GRE and/or E2 binding site in the HPV promoter in a hormone-dependent or independent manner, respectively.

Risperidone modulates the cytokine and chemokine release of dendritic cells and induces TNF-α-directed cell apoptosis in neutrophils.

Antipsychotic drugs (APDs) that bind mainly to the dopamine D2 receptor or the type II 5-HT receptor have been used to ease the symptoms of schizophrenia. Several studies have reported that APDs can also regulate the immune response. Dendritic cells (DCs) are the major antigen-presenting cells in the immune system. DCs can release 5-HT and dopamine to modulate T-cell activation and differentiation. In this study, we use the monocyte-derived DCs to investigate the drug effects of typical APD (haloperidol) and atypical APD (risperidone) on DCs in vitro. Our studies revealed that only risperidone but not haloperidol affected the cytokine and chemokine production of mature DCs. Risperidone increased the production of IL-10 and MDC as well as the proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, but decreased the production of IP-10 and IL-12. Furthermore, the exposure of DCs to risperidone led to lower IFN-γ production by T-cells. The results suggested that risperidone can modulate the DCs' immune function by inhibiting the potent Th1 cytokines and increasing the potent Th2 cytokines. In addition, the production of TNF-α by risperidone-treated mature DCs will induce the death of neutrophils.

Lentiviral short hairpin RNA screen of human kinases and phosphatases to identify potential biomarkers in oral squamous cancer cells.

Oral carcinoma is a serious public health problem and the leading cause of head and neck cancer mortality worldwide. Moreover, oral cancer patients often present symptoms at a late stage and show a high recurrence rate after treatment. Therefore, there is an urgent need to identify novel biomarkers for early diagnosis or clinical oral cancer therapy. In this study, we employed a subset of lentiviral short hairpin RNAs targeted against various kinases and phosphatases, designed by The RNAi Consortium, to screen systemically and in a high-throughput manner for potential growth regulators of oral cancer cells. The screen revealed a total of 50 candidate genes, for which more than 90% of growth inhibition in human oral squamous cancer HSC-3 cells was obtained. Furthermore, bioinformatic analysis of these candidate genes identified transforming growth factor-ß receptor type II- and fms-related tyrosine kinase 3-related molecular pathways that are involved in NF-κB-mediated growth of HSC-3 cells. These candidate genes may be potential biomarkers for early diagnosis of oral cancer. In addition, these candidate genes represent potential targets for anticancer drug design helping to develop a personalized treatment to combat oral cancer.

Antipsychotic drugs suppress the AKT/NF-κB pathway and regulate the differentiation of T-cell subsets.

Antipsychotic drugs (APDs) are commonly used to ease the symptoms of schizophrenia; however, these same drugs also have an effect on the human immune system. Our previous studies have shown that risperidone and clozapine effectively decrease the production of IFN-γ for CD4(+) T-cells in PBMC. In contrast, haloperidol causes an increase in the production of IFN-γ for CD4(+) T-cells in PBMC. In this study we show that risperidone and clozapine can reduce Th1 cell differentiation and T-bet expression. The differentiation of Th1 cells was reduced in clozapine or risperidone treated PBMC by inhibiting the phosphorylation of AKT but not STAT-4. Typical APD, haloperidol, had the opposite effect in regulating T cell differentiation when compared with atypical APDs including risperidone and clozapine. Haloperidol decreased the expression of GATA-3, a Th2-related transcription factor, by inhibiting NF-κB activation rather than STAT-6 phosphorylation and thus decreased Th2 differentiation. In addition, chronic risperidone and clozapine treatment reduces the IFN-γ producing CD4(+) T-cell population within PBMC. In conclusion, this study suggests that APDs do indeed regulate the body's immune response and therefore all APDs should have their own patent in regulating immune responses.

Homocysteine induces smooth muscle cell proliferation through differential regulation of cyclins A and D1 expression.

The mechanism of homocysteine-induced cell proliferation in human vascular smooth muscle cells (SMCs) remains unclear. We investigated the molecular mechanisms by which homocysteine affects the expression of cyclins A and D1 in human umbilical artery SMCs (HUASMCs). Homocysteine treatment induced proliferation of HUASMCs and increased the expression levels of cyclins A and D1. Knocking down either cyclin A or cyclin D1 by small interfering RNA (siRNA) inhibited homocysteine-induced cell proliferation. Furthermore, treatment with extracellular signal-related kinase (ERK) inhibitor (PD98059) and dominant negative Ras (RasN17) abolished homocysteine-induced cyclin A expression; and treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) and mammalian target of rapamycin (mTOR) inhibitor (rapamycin) attenuated the homocysteine-induced cyclin D1 expression. Homocysteine also induced transient phosphorylation of ERK, Akt, and p70 ribosomal S6 kinase (p70S6K). Neutralizing antibody and siRNA for ß1 integrin blocked cell proliferation, expression of cyclins A and D1, and phosphorylation of ERK and Akt. In conclusion, homocysteine-induced differential activation of Ras/ERK and PI3K/Akt/p70S6K signaling pathways and consequent expression of cyclins A and D1 are dependent on ß1 integrin. Homocysteine may accelerate progression of atherosclerotic lesions by promoting SMC proliferation.

Breast cancer amplified sequence 2, a novel negative regulator of the p53 tumor suppressor.

Breast cancer amplified sequence 2 (BCAS2) was reported previously as a transcriptional coactivator of estrogen receptor. Here, we report that BCAS2 directly interacts with p53 to reduce p53 transcriptional activity by mildly but consistently decreasing p53 protein in the absence of DNA damage. However, in the presence of DNA damage, BCAS2 prominently reduces p53 protein and provides protection against chemotherapeutic agent such as doxorubicin. Deprivation of BCAS2 induces apoptosis in p53 wild-type cells but causes G(2)-M arrest in p53-null or p53 mutant cells. There are at least two apoptosis mechanisms induced by silencing BCAS2 in wild-type p53-containing cells. Firstly, it increases p53 retention in nucleus that triggers the expression of apoptosis-related genes. Secondly, it increases p53 transcriptional activity by raising p53 phosphorylation at Ser(46) and decreases p53 protein degradation by reducing p53 phosphorylation at Ser(315). We show for the first time that BCAS2, a small nuclear protein (26 kDa), is a novel negative regulator of p53 and hence a potential molecular target for cancer therapy.

Difference in the regulation of IL-8 expression induced by uropathogenic E. coli between two kinds of urinary tract epithelial cells.

Bacterial adherence to epithelial cells is a key virulence trait of pathogenic bacteria. The type 1 fimbriae and the P-fimbriae of uropathogenic Escherichia coli (UPEC) have both been described to be important for the establishment of urinary tract infections (UTI). To explore the interactions between the host and bacterium responsible for the different environments of UPEC invasion, we examined the effect of pH and osmolarity on UPEC strain J96 fimbrial expression, and subsequent J96-induced interleukin-8 (IL-8) expression in different uroepithelial cells. The J96 strain grown in high pH with low osmolarity condition was favorable for the expression of type 1 fimbriae; whereas J96 grown in low pH with high osmolarity condition was beneficial for P fimbriae expression. Type 1 fimbriated J96 specifically invaded bladder 5637 epithelial cells and induced IL-8 expression. On the contrary, P fimbriated J96 invaded renal 786-O epithelial cells and induced IL-8 expression effectively. Type 1 fimbriated J96-induced IL-8 induction involved the p38, as well as ERK, JNK pathways, which leads to AP-1-mediated gene expression. P fimbriated J96-induced augmentation of IL-8 expression mainly involved p38-mediated AP-1 and NF-kappaB transcriptional activation. These results indicate that different expression of fimbriae in J96 trigger differential IL-8 gene regulation pathways in different uroepithelial cells.

The N-terminal domain of EBNA1 acts as a suppressor of the HER2/neu oncogene.

HER2/neu oncogene-mediated malignancy is clearly associated with various human cancers. Therefore, HER2/neu targeting is an effective approach to cancer therapy. We have previously demonstrated that Epstein-Barr virus nuclear antigen-1 (EBNA1) can suppress HER2/neu oncogene expression, although EBNA1 itself has oncogenic potential. Here, we found that the N-terminal domain of EBNA1 alone, named EBNA1-NT, which contains the N-terminal region of amino acid residues 1-86 of EBNA1, is required and sufficient to suppress HER2/neu oncogene expression at the transcriptional level. Furthermore, in EBNA1-NT-transfected HER2/neu-overexpressing cells, we found EBNA1-NT could down-regulate the endogenous production of p185(HER2/neu), lower transformation ability, sensitize paclitaxel-induced apoptosis and decrease tumorigenic potential. These data suggest that EBNA1-NT may act as a repressor of the HER2/neu oncogene.

Perioperative thrombotic occlusion of left external iliac artery during anterior lumbar interbody fusion.

We report a case of thrombotic occlusion of left external iliac artery during the procedure of anterior lumbar interbody fusion. The diagnosis was confirmed by computed tomography angiography. The patient also developed severe rhabdomyolysis postoperatively. In spite of receiving emergent thromboendarterectomy, the patient expired on postoperative day 3. This report attempts to remind spinal surgeons and anesthesiologists of this rare but potentially fatal complication, and discuss the possible mechanism, management, and prevention.