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    15 September 2013, Volume 4 Issue 3
    Review Articles
    S100B protein in serum is elevated after global cerebral ischemic injury
    Bao-di Sun, Hong-mei Liu, Shi-nan Nie
    2013, 4(3):  165-168.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.001
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    BACKGROUND: S100B protein in patients with cardiac arrest, hemorrhagic shock and other causes of global cerebral ischemic injury will be dramatically increased. Ischemic brain injury may elevate the level of serum S100B protein and the severity of brain damage.
    METHODS: This article is a critical and descriptive review on S100B protein in serum after ischemic brain injury. We searched Pubmed database with key words or terms such as "S100B protein", "cardiac arrest", "hemorrhagic shock" and "ischemia reperfusion injury" appeared in the last five years.
    RESULTS: S100B protein in patients with cardiac arrest, hemorrhagic shock and other causes of ischemic brain injury will be dramatically increased. Ischemic brain injury elevated the level of serum S100B protein, and the severity of brain damage.
    CONCLUSION: The level of S100B protein in serum is elevated after ischemic brain injury, but its mechanism is unclear.

    The Acinetobacter baumannii group:a systemic review
    Hua-zhong Zhang, Jin-song Zhang, Li Qiao
    2013, 4(3):  169-174.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.002
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    BACKGROUND: The Acinetobacter baumannii group, includingAcinetobacter baumannii, Acinetobacter genomospecies 3 and 13TU, is phenotypically indistinguishable and uniformly identified as Acinetobacter baumannii by laboratories of clinical microbiology. This review aimed to demonstrate the differences among them.
    METHODS: Literatures associated with the Acinetobacter baumannii group were identified and selected from PubMed databases and relevant journals.
    RESULTS: Acinetobacter genospecies 3 and 13TU possess a certain proportion in clinical isolates. There were considerable differences in epidemiologic features, clinical manifestations, antimicrobial resistances and therapeutic options among the Acinetobacter baumannii group. Compared with Acinetobacter genomospecies 3 and 13TU, Acinetobacter baumannii with a higher resistance to antimicrobial agents are easier to be treated inappropriately, and present a worse outcome in patients.
    CONCLUSION: The Acinetobacter baumannii group comprises three distinct clinical entities, and their clinical value are not equal.

    Original Articles
    Is routine pregnancy test necessary in women of reproductive age admitted to the emergency department?
    Özlem Köksal, Fatma Özdemir, Erol Armağan, Nuran Öner, Pınar Çinar Sert, Deniz Sigirli
    2013, 4(3):  175-178.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.003
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    BACKGROUND: This study aimed to determine the necessity of pregnancy test in women of reproductive age admitted to emergency department (ED) in routine practice.
    METHODS: We retrospectively reviewed the records of patients who presented to the ED between January 1, 2006 and December 31, 2010 and received a pregnancy test.
    RESULTS: The median age of 1 586 patients enrolled into the study was 27 years. Of these patients, 19.55% had a positive result of pregnancy test. The most common complaint at admission was abdominal pain in 60.15% of the patients, and pregnancy test was prescribed. 15.83% of the patients with abdominal pain had a positive result of pregnancy test. Of the patients, 30.64% had nausea-vomiting at admission, and 11.52% had a positive result of pregnancy test. When other complaints were considered, the most commonly observed complaints were non-specific symptoms such as dizziness, malaise and respiratory problems. Of the patients, 70.93% were not remembering the date of last menstruation, and 9.51% showed a positive result of pregnancy test. Urinary tract infection (UTI) was commonly diagnosed with an incidence of 17.65%, which was followed by non-specific abdominal pain (NSAP) (16.77%) and gastrointestinal disorders such as gastritis and peptic ulcer (6.87%). Of the patients, 88.40% were discharged from ED, and 11.60% were hospitalized.
    CONCLUSION: Pregnancy test should be given to women of reproductive age as a routine practice in ED in developing countries like Turkey.

    A continuous quality improvement project to reduce medication error in the emergency department
    Sara BC Lee, Larry LY Lee, Richard SD Yeung, Jimmy TS Chan
    2013, 4(3):  179-182.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.004
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    BACKGROUND: Medication errors are a common source of adverse healthcare incidents particularly in the emergency department (ED) that has a number of factors that make it prone to medication errors. This project aims to reduce medication errors and improve the health and economic outcomes of clinical care in Hong Kong ED.
    METHODS: In 2009, a task group was formed to identify problems that potentially endanger medication safety and developed strategies to eliminate these problems.
    RESULTS: Responsible officers were assigned to look after seven error-prone areas. Strategies were proposed, discussed, endorsed and promulgated to eliminate the problems identified. A reduction of medication incidents (MI) from 16 to 6 was achieved before and after the improvement work.
    CONCLUSION: This project successfully established a concrete organizational structure to safeguard error-prone areas of medication safety in a sustainable manner.

    Factors influencing outcomes after cardiopulmonary resuscitation in emergency department
    Ji-ke Xue, Qiao-yun Leng, Yu-zhi Gao, Shou-quan Chen, Zhang-ping Li, Hui-ping Li, Wei-jia Huang, Jun-yan Cheng, Jie Zhang, Ai-wen He
    2013, 4(3):  183-189.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.005
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    BACKGROUND: The outcome of cardiopulmonary resuscitation (CPR) may depend on a variety of factors related to patient status or resuscitation management. To evaluate the factors influencing the outcome of CPR after cardiac arrest (CA) will be conducive to improve the effectiveness of resuscitation. Therefore, a study was designed to assess these factors in the emergency department (ED) of a city hospital.
    METHODS: A CPR registry conforming to the Utstein-style template was conducted in the ED of the First Affiliated Hospital of Wenzhou Medical College from January 2005 to December 2011. The outcomes of CPR were compared in various factors groups. The primary outcomes were rated to return of spontaneous circulation (ROSC), 24-hour survival, survival to discharge and discharge with favorable neurological outcomes. Univariate analysis and multivariable logistic regression analysis were performed to evaluate factors associated with survival.
    RESULTS: A total of 725 patients were analyzed in the study. Of these patients, 187 (25.8%) had ROSC, 100 (13.8%) survived for 24 hours, 48 (6.6%) survived to discharge, and 23 (3.2%) survived to discharge with favorable neurologic outcomes. A logistic regression analysis demonstrated that the independent predictors of ROSC included traumatic etiology, first monitored rhythms, CPR duration, and total adrenaline dose. The independent predictors of 24-hour survival included traumatic etiology, cardiac etiology, first monitored rhythm and CPR duration. Previous status, cardiac etiology, first monitored rhythms and CPR duration were included in independent predictors of survival to discharge and neurologically favorable survival to discharge.
    CONCLUSIONS: Shockable rhythms, CPR duration ≤15 minutes and total adrenaline dose ≤5 mg were favorable predictors of ROSC, whereas traumatic etiology was unfavorable. Cardiac etiology, shockable rhythms and CPR duration ≤15 minutes were favorable predictors of 24-hour survival, whereas traumatic etiology was unfavorable. Cardiac etiology, shockable rhythms, CPR duration ≤15 minutes were favorable predictors of survival to discharge and neurologically favorable survival to discharge, but previous terminal illness or multiple organ failure (MOF) was unfavorable.

    Urokinase-type plasminogen activator receptor as a predictor of poor outcome in patients with systemic inflammatory response syndrome
    Xiao-ling Wu, Ding Long, Li Yu, Jun-hui Yang, Yuan-chao Zhang, Feng Geng
    2013, 4(3):  190-195.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.006
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    BACKGROUND: Urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR) are known as important factors, which mediate a variety of functions in terms of vascular homeostasis, inflammation and tissue repair. However, their role in systemic inflammatory response syndrome (SIRS) has been less well studied. This study aimed to test the hypothesis that the abnormalities of fibrinolysis and degradation of extracellular matrix mediated by uPA and uPAR are directly related to the patients with SIRS. We therefore analyzed their role and clinicopathological significance in patients with SIRS.
    METHODS: A case-control study was conducted with 85 patients who were divided into two groups according to the diagnostic criteria of SIRS: SIRS group (n=50) and non-SIRS group (n=35). The SIRS group was divided into MODS group (n=26) and non-MODS group (n=24) by their severity, and survival group (n=35) and non-survival group (n=15) by their prognosis. Another 30 healthy adults served as normal controls. uPA and uPAR in plasma were detected by commercial enzyme-linked immunosorbent assay (ELISA) kits.
    RESULTS: The plasma level of uPA was lower in the SIRS group than in the non-SIRS group and controls (P<0.001 and P<0.001). It was lower in sepsis patients and the MODS group than in the non-sepsis patients and the non-MODS patients (all P<0.05). However, there was no difference in uPA level between survivors and non-survivors (P>0.05). The plasma level of uPAR increased in the SIRS group compared with the non-SIRS group and controls (P<0.001 and P<0.001). There was a significant elevation of uPAR in sepsis patients, MODS patients and non-survivors as compared with non-sepsis patients, non-MODS patients and survivors respectively (all P<0.05). Plasma uPAR levels were positively correlated with APACHE II score (r=0.575,P<0.001) and SOFA score (r=0.349, P=0.013). AUCs for the prediction of SIRS mortality were 0.67 and 0.51, respectively, for uPA and uPAR.
    CONCLUSION: uPAR could be a predictor of poor outcome in patients with SIRS.

    Clinical analysis of central venous catheter-related infections in patients in the emergency ICU
    Min Chen, Ri-jin Zhu, Feng Chen, Xiao-pin Wang, Jun Ke
    2013, 4(3):  196-200.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.007
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    BACKGROUND: Catheter-related infection (CRI) of the central vein is a common cause of nosocomial infection. This study was undertaken to investigate the pathogen culturing and risk factors of CRI in emergency intensive care unit (EICU) in order to provide the beneficial reference.
    METHODS: From January 2008 to December 2010, a total of 1 363 patients were subjected to catheterization. In these patients, the peak CRI rate of the patients was determined by bacterial cultivation and blood bacterial cultivation.
    RESULTS: CRI happened in 147 of the 1 363 patients using the central venous catheter. The peak rate of CRI was 10.79%, with an incidence of 3.05 episodes per 1 000 catheter days. Of the 147 patients, 46.94% had gram-negative bacilli, 40.14% had gram-positive cocci, and 12.92% had fungi. Unconditional logistic regression analysis suggests that multiple catheterization, femoral vein catheterization, the application of multicavity catheter, and the duration of catheterization were the independent risk factors for CRI.
    CONCLUSION: The risk factors for catheter-related infections should be controlled to prevent the occurrence of nosocomial infection.

    Glycated hemoglobin A1C and diabetes mellitus in critically ill patients
    Hai-yan Zhang, Cai-jun Wu, Chun-sheng Li
    2013, 4(3):  201-204.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.008
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    BACKGROUND: Hyperglycemia has been detected in many critically ill patients in the department of emergency medicine. But its mechanism and prognosis have not been well elucidated. In this study, we measured the serum level of glycated hemoglobin A1C (HbA1c) in critically ill patients to evaluate the effects of hyperglycemia on the prognosis of the patients.
    METHODS: A total of 826 critically ill patients, who had been treated at the Department of Emergency Medicine of Chaoyang Hospital during October 2006 and November 2007, were divided into a diabetes mellitus group (n=184) and a non-diabetes mellitus group (642) according to whether they had diabetes mellitus. Fasting glucose and HbA1c were measured in all patients. Those in the diabetes mellitus group were further assigned to a drug therapy subgroup and a non-drug therapy subgroup; the serum level of HbA1c and its relationship with short-term outcome were evaluated.
    RESULTS: Fasting glucose increased in 78.8% of the patients (88.6% in the diabetes mellitus group, and 75.9% in the non-diabetes mellitus group,P<0.05), and HbA1c was elevated in 45.5% of the patients (78.3% in the diabetes mellitus group, and 36.1% in the non-diabetes mellitus group, P<0.01). Fasting glucose, HbA1c and 28-day mortality were improved more significantly (P<0.01) in the drug therapy subgroup than in the non-drug therapy subgroup. The 28-day mortality was more significantly different in patients with fasting blood glucose >8.33 mmol/L than in those with fasting blood glucose <8.33 mmol/L.
    CONCLUSIONS: Hyperglycemia of critically ill patients could not totally attribute to stress response, especially in those who have no history of diabetes mellitus. Prognosis of hyperglycemia may vary among critically ill patients.

    Therapeutic effect of recombinant tissue plasminogen activator on acute cerebral infarction at different times
    Ming Liu, Hai-rong Wang, Jia-fu Liu, Hao-jun Li, Shen-xing Chen, Sha Shen, Shu-ming Pan
    2013, 4(3):  205-209.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.009
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    BACKGROUND: The study aimed to compare the therapeutic effect of recombinant tissue plasminogen activator (rt-PA) on the onset of acute cerebral infarction (ACI) at different time points of the first 6 hours.
    METHODS: A retrospective analysis was conducted in 74 patients who received rt-PA thrombolysis treatment within 4.5 hours after ACI and another 15 patients who received rt-PA thrombolysis treatment between 4.5-6 hours after ACI.
    RESULTS: National Institute of Health Stroke Scale (NIHSS) scores were statistically decreased in both groups (P>0.05) at 24 hours and 7 days after ACI. There was no significant difference in modified ranking scores and mortality at 90 days after the treatment between the two groups (P>0.05).
    CONCLUSIONS: The therapeutic effect and mortality of rt-PA treatment in patients with ACI between 4.5-6 hours after the onset of the disease were similar to those in patients who received rt-PA within 4.5 hours after the onset of this disease. Therefore, intravenous thrombolytic therapy for ACI within 4.5-6 hours after ACI was effective and safe.

    Upregulated expression of S100A8 in mice brain after focal cerebral ischemia reperfusion
    Peng Sun, Qian Li, Qing Zhang, Li Xu, Ji-yuan Han
    2013, 4(3):  210-214.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.010
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    BACKGROUND: Recent studies have showed that S100A8 has been implicated in the pathobiology of inflammatory disorders, and that cerebral ischemia reperfusion (I/R) rapidly activates inflammation responses via Toll-like receptor 4 (TLR4). This study aimed to explore the expression of S100A8 and the relationship between S100A8 and TLR4 in focal cerebral ischemia reperfusion injury.
    METHODS: C3H/HeJ mice (n=30) and C3H/HeN mice (n=30) were divided randomly into a C3H/HeJ model group (n=18), a C3H/HeJ control group (n=12), a C3H/HeN model group (n=18), and a C3H/HeN control group (n=12). Middle cerebral artery I/R model in mice was produced using a thread embolism method. The brains of the mice were collected after ischemia for 1 hour and reperfusion for 12 hours. Stroke outcome was evaluated by determination of infarct volume and assessment of neurological impairment scores. Brain injury after cerebral I/R was observed by an optical microscope after TTC and HE dyeing. The immunofluorescence technique and real time PCR were used to test the expression level of S100A8 in brain damage.
    RESULTS: Compared with C3H/HeN mice, TLR4-deficient mice (C3H/HeJ) had lower infarct volumes and better outcomes in neurological tests. The levels of S100A8 increased sharply in the brains of mice after I/R injury. In addition, mice that lacked TLR4 (C3H/HeJ) had lower expression of I/R-induced S100A8 than C3H/HeN mice in the model group, indicating that a close relationship might exist between the levels of S100A8 and TLR4.
    CONCLUSION: S100A8 interaction with TLR4 might be involved in brain damage and in inflammation triggered by I/R injury.

    Cardioprotective effect of erythropoietin on sepsis-induced myocardial injury in rats
    Yan-jun Qin, Xin-liang Zhang, Yue-qing Yu, Xiao-hua Bian, Shi-min Dong
    2013, 4(3):  215-223.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.011
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    BACKGROUND: Sepsis-induced myocardial injury is one of the major predictors of morbidity and mortality of sepsis. The cytoprotective function of erythropoietin (EPO) has been discovered and extensively studied. However, the cardioprotective effects of EPO on sepsis-induced myocardial injury in the rat sepsis model has not been reported.
    METHODS: The rat models of sepsis were produced by cecal ligation and perforation (CLP) surgery. Rats were randomly (random number) assigned to one of three groups (n=8 for each group): sham group, CLP group and EPO group (1000 IU/kg erythropoietin). Arterial blood was withdrawn at 3, 6, 12, and 24 hours after CLP. cTnI, BNP, CK-MB, LDH, AST, TNF-α, IL-6, IL-10, and CRP were tested by the ELISA assay. Changes of hemodynamic parameters were recorded at 3, 6, 12, 24 hours after the surgery. Histological diagnosis was made by hematoxylin and eosin. Flow cytometry was performed to examine cell apoptosis, myocardium mitochondrial inner membrane potential, and NF-κB (p65). Survival rate at 7 days after CLP was recorded.
    RESULTS: In the CLP group, myocardial enzyme index and inflammatory index increased at 3, 6, 12 and 24 hours after CLP compared with the sham group, and EPO significantly blocked the increase. Compared with the CLP group, EPO significantly improved LVSP, LV +dp/dtmax, LV -dp/dtmin, and decreased LVEDP at different time. EPO blocked the reduction of mitochondrial transmembrane potential, suppressed the cardiomyocyte apoptosis, inhibited the activation of NF-κB, and reduced the production of proinflmmatory cytokines. No difference in the survival rate at 7 days was observed between the CLP group and the EPO group.
    CONCLUSION: Exogenous EPO has cardioprotective effects on sepsis-induced myocardial injury.

    Repair of damaged intestinal mucosa in a mouse model of sepsis
    Rui-ming Chang, Li-qiang Wen, Jian-xing Chang, Yu-ru Fu, Zhi-peng Jiang, Shuang Chen
    2013, 4(3):  223-228.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.012
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    BACKGROUND: The intestine is not only the main target attacked by sepsis but also the vital organ which mediated sepsis. The recovery of the damaged intestinal barrier structure and function is related to the occurrence and outcome of multiple organ dysfunction syndrome (MODS). How to protect and reduce the damage of the intestinal mucosa and how to promote the reconstruction of the intestinal mucosa have been the important topics in sepsis for many years. This study aimed to investigate the influential factors of intestinal mucosal reconstruction after intestinal epithelial injury in vivo in a mouse model of sepsis.
    METHODS: Mice were subjected to cecal ligation and puncture (CLP) for induction of sepsis to assess intestinal mucosal damage, epithelial cell apoptosis, and transformed number of goblet cells, and to detect the concentration of TNF-α, IL-1 and TGF-β1 and TFF3 (trefoil factor 3) expression in the small intestinal mucosa. All above were performed by HE staining, western blot, ELISA and immunohistochemistry respectively. The experimental animals were divided into a sepsis group and a sham-operation group. The animals with sepsis were separately killed at 6 (7 animals), 24 (7 animals) and 48 hours (7 animals) after CLP.
    RESULTS: Injured intestinal mucosa was observed in the 3 groups under a light microscope, in which damage scores in the 24-hour and 48-hour groups were higher than in the 6-hour group and no difference was found between the two groups. Moreover, less of goblet cells or other epithelial cells adjacent to the injured surface migrated into the wound to cover the denuded area. The number of goblet cells was substantially decreased in the three CLP groups compared with the sham-operation group. Protein levels of IL-1 and TNF-α were significantly increased by 3-4 fold at all time points when compared with the sham-operation group, and cleaved caspase-3 by 4 fold. Although TFF3 expression was modestly increased for 6 hours after the onset of CLP, it appeared to decline at 24 hours and 48 hours as shown by Western blot. A similar tendency was observed upon TGF-β1, i.e. the protein level was not elevated at 24 hours and 48 hours, but increased modestly at 6 hours.
    CONCLUSIONS: Sepsis from CLP shows less restitution on the surface of injured intestinal mucosa. There is evidence that both constant inflammatory reaction and epithelial cell apoptosis may affect mucosal reestablishment of the intestine at the onset of sepsis. Mucosa after severe sepsis showed the state of high inflammation, and declined goblet cell function and mucosal reconstruction, which affected the repair of damaged intestinal barrier. Constant inflammatory reaction, and declined goblet cell function and mucosal reconstruction ability may affect the reestablishment of intestinal mucosa at the onset of sepsis.

    Case Reports
    Infective endocarditis complicated with cerebral and splenic infarction in a hemodialysis patient
    Ozge Duman Atilla, Zeynep Temizyurek, Egemen Kirman
    2013, 4(3):  229-231.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.013
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    BACKGROUND: Infective endocarditis (IE) has a high risk of morbidity and mortality. Complications are often due to systemic embolization. We treated a 47-year-old hemodialysis man with infective endocarditis complicated with cerebral and splenic infarction.
    METHODS: The patient was brought to the emergency department because of altered mental status and fecal incontinence. Although he did not meet the Duke Criteria for IE diagnosis, clinical suspicions of IE warranted further diagnostic studies. Magnetic resonance imaging of the brain revealed cerebral infarction with abnormal neurological findings. An abdominal computerized tomography revealed an incidental and unexpected splenic infarction without physical findings. Echocardiography revealed a vegetative growth (-1.2×1 cm) over the mitral posterior leaflet with severe mitral valve regurgitation. Based on these results, the patient was diagnosed with IE complicated with severe cerebral and splenic infarction.
    RESULTS: The patient was treated with intravenous teicoplanin including gentamicin, subcutaneous low molecular weight heparin, and oral acetylsalicylic acid. Mitral valve replacement surgery was performed after the patient improved clinically.
    CONCLUSION: Emergency physicians should be aware of the life-threatening complications of IE, which may be presented subtly or without clinical evidence.

    Mesenteric infarction due to iatrogenic polycythemia
    Katrina Skoog, Marie Carmelle-Elie, Kevin Ferguson
    2013, 4(3):  232-234.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.014
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    BACKGROUND: Polycythemia vera is defined as a chronic myeloproliferative disorder characterized by increased red blood cell count. There have been no reports on mesenteric thrombosis resulting from iatrogenic polycythemia.
    METHODS: We present a patient with a history of non-small cell lung cancer undergoing maintenance oral chemotherapy on tarceva and adjunctive use of procrit. The patient presented to our emergency department with an acute abdomen and was found to have ischemic bowel from unmonitored procrit, which lead to hyperviscosity of blood and mesenteric infarction.
    RESULTS: The patient remained intubated with ventilator support. He refused a tracheostomy. He continued on feeding through the J port of the nasojejunal tube. His white cell count, and hematocrit and creatinine levels remained normal. Procrit use and chemotherapy were not restarted. He was transferred to a subacute nursing facility for further treatment.
    CONCLUSIONS: Procrit and other erythropoiesis stimulating drugs can cause significant morbidity and mortality with an increased risk of cardiovascular events, gastrointestinal bleeding, thromboembolism and stroke. This case report suggests that without closely monitoring hematocrit levels, epoetin may also be associated with an increased risk of mesenteric infarction.

    Free tubercular perforation of the ileum
    Sanjay Gupta, Mayank Jayant, Robin Kaushik
    2013, 4(3):  235-236.  doi:10.5847/wjem.j.issn.1920-8642.2013.03.015
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    BACKGROUND: Peritonitis secondary to small bowel perforation is a common surgical emergency seen across the globe.
    METHODS: A young male patient presented with ileal perforation that was repaired primarily. He recovered uneventfully after the operation.
    RESULTS: Histopathology of the margins of the perforation revealed tuberculosis. A search for evidence of a primary focus of tuberculosis was unsuccessful. The patient was started on anti-tubercular therapy and he was followed up with good results.
    CONCLUSION: This present case underscores the importance of biopsy specimens taken from the margins of patients with ileal perforation to avoid the misdiagnosis of such condition.

    Instructions for Authors
    Instructions for Authors
    Editorial Office
    2013, 4(3):  237-240. 
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    World Journal of Emergency Medicine (WJEM), a peerreviewed quarterly journal based at the Second Affiliated Hospital of Zhejiang University School of Medicine, China, publishes articles of interest to both clinicians and researchers involving emergency medicine around the world. It focuses on content relevant to clinical practice and research, laboratory studies, continuing education about emergency medicine.