Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2015, Volume 9 Issue 1
CT scan was performed 1 week after cryoablation to evaluate the efficacy of treatment. In the selected case, the 5.8 cm HCC lesion was totally replaced by hypovascular necrotic tissue with hypervascular inflammatory rim indicating a complete ablation of the tumor with a single cryoablation session. (Courtesy of Dr. Yongping Yang, See Pages by Guanghua Rong et al. for more information.)
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REVIEW
Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia
Ching-Hon Pui
Front. Med.. 2015, 9 (1): 1-9.  
https://doi.org/10.1007/s11684-015-0381-3

Abstract   HTML   PDF (143KB)

With the cure rate of childhood acute lymphoblastic leukemia (ALL) approaching 90%, further improvement in the treatment outcome and quality of life of patients will require better understanding of the mechanisms of drug resistance, identifying new leukemic cell genetic lesions that are amendable to available target therapy, and optimizing treatment based on host pharmacodynamics and pharmacogenomics. Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications. In this regard, several novel fusion transcripts are responsive to ABL tyrosine kinase inhibitors and potentially to JAK inhibitors. Genome-wide analyses have also unraveled the role of inherited cancer predisposing genes and small nucleotide polymorphisms of several genes in the development of childhood ALL. These advances promise to lead to more sophisticated personalized treatment strategies in the near future.

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Th17 Cells in autoimmune diseases
Lei Han,Jing Yang,Xiuwen Wang,Dan Li,Ling Lv,Bin Li
Front. Med.. 2015, 9 (1): 10-19.  
https://doi.org/10.1007/s11684-015-0388-9

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Th17 cells are a new subset of CD4+ T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sj?gren’s syndrome, inflammatory bowel disease, and multiple sclerosis.

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Implantation of human umbilical cord mesenchymal stem cells for ischemic stroke: perspectives and challenges
Yingchen Li,Guoheng Hu,Qilai Cheng
Front. Med.. 2015, 9 (1): 20-29.  
https://doi.org/10.1007/s11684-014-0371-x

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Ischemic stroke is a focal cerebral insult that often leads to many adverse neurological complications severely affecting the quality of life. The prevalence of stroke is increasing throughout the world, while the efficacy of current pharmacological therapies remains unclear. As a neuroregenerative therapy, the implantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) has shown great possibility to restore function after stroke. This review article provides an update role of hUC-MSCs implantation in the treatment of ischemic stroke. With the unique “immunosuppressive and immunoprivilege” property, hUC-MSCs are advised to be an important candidate for allogeneic cell treatment. Nevertheless, most of the treatments are still at primary stage and not clinically feasible at the current time. Several uncertain problems, such as culture conditions, allograft rejection, and potential tumorigenicity, are the choke points in this cellular therapy. More preclinical researches and clinical studies are needed before hUC-MSCs implantation can be used as a routinely applied clinical therapy.

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Three-dimensional reconstruction of light microscopy image sections: present and future
Yuzhen Wang,Rui Xu,Gaoxing Luo,Jun Wu
Front. Med.. 2015, 9 (1): 30-45.  
https://doi.org/10.1007/s11684-014-0337-z

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Three-dimensional (3D) image reconstruction technologies can reveal previously hidden microstructures in human tissue. However, the lack of ideal, non-destructive cross-sectional imaging techniques is still a problem. Despite some drawbacks, histological sectioning remains one of the most powerful methods for accurate high-resolution representation of tissue structures. Computer technologies can produce 3D representations of interesting human tissue and organs that have been serial-sectioned, dyed or stained, imaged, and segmented for 3D visualization. 3D reconstruction also has great potential in the fields of tissue engineering and 3D printing. This article outlines the most common methods for 3D tissue section reconstruction. We describe the most important academic concepts in this field, and provide critical explanations and comparisons. We also note key steps in the reconstruction procedures, and highlight recent progress in the development of new reconstruction methods.

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Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review
Amma Owusu-Ansah,Sung Hee Choi,Agne Petrosiute,John J. Letterio,Alex Yee-Chen Huang
Front. Med.. 2015, 9 (1): 46-56.  
https://doi.org/10.1007/s11684-015-0375-1

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Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso-occlusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived- 2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.

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RESEARCH ARTICLE
Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells
Yi Liang,Qisheng Feng,Jian Hong,Futuo Feng,Yi Sang,Wenrong Hu,Miao Xu,Roujun Peng,Tiebang Kang,Jinxin Bei,Yixin Zeng
Front. Med.. 2015, 9 (1): 57-62.  
https://doi.org/10.1007/s11684-015-0389-8

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The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

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Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases
Guanghua Rong,Wenlin Bai,Zheng Dong,Chunping Wang,Yinying Lu,Zhen Zeng,Jianhui Qu,Min Lou,Hong Wang,Xudong Gao,Xiujuan Chang,Linjing An,Yan Chen,Yongping Yang
Front. Med.. 2015, 9 (1): 63-71.  
https://doi.org/10.1007/s11684-014-0342-2

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Cryoablation is a less prevalent percutaneous ablative therapy for hepatocellular carcinoma (HCC), and current evidence about its usefulness is limited. We report our experience in treating 1595 HCC cases with percutaneous cryoablation to give a comprehensive profile about the effectiveness, safety and long-term outcome of this therapy. From January 2003 to December 2013, 1595 patients with 2313 HCC nodules were ablated with 2945 cryoablation sessions in our center. Complete ablation was achieved in 1294 patients for 1893 nodules with a mean diameter of 3.4±2.2 cm. The complete ablation rate was 81.2%, 99.4%, 94.4%, and 45.6% in all tumors, tumors<3 cm, tumors<5 cm, and tumors>5 cm, respectively. Major complications were observed after 80 (3.4%) of the 2945 cryoablations and minor complications were observed after 330 cryoablations with no treatment-related deaths. After a median follow-up of 33.4 months, 937 patients developed different types of recurrence. The 5- and 10-year overall survival was 25.7% and 9.2%, respectively. Cryoablation showed reliable safety and efficacy and should be considered as a promising technique, particularly when a large zone of ablation is required.

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Role of salivary matrix metalloproteinase-8 (MMP-8) in chronic periodontitis diagnosis
Namita Gupta,N.D. Gupta,Akash Gupta,Saif Khan,Neha Bansal
Front. Med.. 2015, 9 (1): 72-76.  
https://doi.org/10.1007/s11684-014-0347-x

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Periodontitis is an inflammatory disease of the periodontium. Any imbalance between the matrix metalloproteinases (MMPs) secreted by neutrophils and tissue inhibitors initiates the destruction of collagen in gum tissue, leading to chronic periodontitis. This study aimed to correlate salivary levels of MMP-8 and periodontal parameters of chronic periodontitis to establish MMP-8 as a noninvasive marker for the early diagnosis of chronic periodontitis. The study involved 40 subjects visiting the periodontic OPD of Dr. Ziauddin Ahmad Dental College and Hospital, located in Aligarh, U.P., India, from 2011 to 2012. The subjects were divided into two groups: group I consisted of 20 periodontally healthy subjects (controls) while group II consisted of 20 patients with chronic periodontitis. Chronic periodontitis was assessed on the basis of several periodontal parameters, including pocket probing depth (PPD), clinical attachment level (CAL), gingival index (GI), and plaque index (PI). Around 3 ml of unstimulated and whole expectorated saliva was collected for MMP-8 estimation by ELISA using Quantikine human total MMP-8 immunoassay kits. Data were analyzed using STATISTICA (Windows version 6) software. Salivary MMP-8 levels of groups I and II were 190.91±143.89 ng/ml and 348.26±202.1 ng/ml, respectively. The MMP-8 levels and periodontal status (PPD, CAL, GI, and PI) of groups I and II showed positive and significant correlations (for PPD, r = 0.63, P<0.001; for CAL, r = 0.54, P<0.001; for GI, r = 0.49, P<0.001; and for PI, r = 0.63, P<0.001). The results of this study demonstrate elevated concentrations of MMP-8 in individuals with chronic periodontitis.

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A new minimally invasive treatment for anal fistula
Rui Zhu,Lin Shen,Caoyuan Wang,Yanping Yang,Rui Chen,Hen Fang,Xiaojuan Xu
Front. Med.. 2015, 9 (1): 77-81.  
https://doi.org/10.1007/s11684-014-0352-0

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In colorectal surgery, eradicating the fistula and maintaining continence are still complex challenges for a colorectal surgeon. A minimally invasive method using a novel device was performed to consecutively treat 14 patients with anal fistula from August 2008 to November 2009. After a follow-up period of 36 months, 13 patients achieved successful closure of their fistula tracts, and recurrence occurred only in one patient. Recurrence was due to the delay of dressing change. No patient had interference with continence, and no major intra- and post-operative complications were identified. Using the novel device with invasive methods can be a promising alternative for managing anal fistulas.

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Reproductive toxicity study with a novel deoxyguanosine analogue (Metacavir) in pregnant SD rats
Qihui Luo,Zhengli Chen,Anchun Cheng,Mingshu Wang,Jing Fang,Xi Peng,Li Tang
Front. Med.. 2015, 9 (1): 82-89.  
https://doi.org/10.1007/s11684-015-0376-0

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Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir (200, 100, 50, 0 mg/kg body weight) during the first 6–15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6–20 pregnant days were significantly different (P<0.01, P<0.05). Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group (P<0.05), while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/(kg·d) (i.e., 40 times the effective dose in rats), Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/(kg·d) there is no teratogenic side effects.

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Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B
Ru Zhang,Qiang Wang,Lin Zhang,Saijuan Chen
Front. Med.. 2015, 9 (1): 90-99.  
https://doi.org/10.1007/s11684-015-0390-2

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Gene therapy provides a potential cure for hemophilia B, and significant progress has been achieved in liver-directed gene transfer mediated by adeno-associated viral vectors. Recent clinical trials involving the use of a self-complementary adeno-associated virus serotype 8-human codon-optimized factor IX (AAV8-hFIXco) vector demonstrated encouraging efficacy with hFIX expression stabilized at 1% to 6% of normal level in patients, but safety concerns related to high vector doses are still present. Thus, further improvement of AAV vectors and hFIX expression cassette may positively contribute to the ultimate success of hemophilia B gene therapy. In this study, to obtain a higher expression level of hFIX that potentiates the coagulant capacity of recipients, human FIX expression vector was optimized by upgrading the codon adaption index and adjusting the GC content, inserting a Kozak sequence (GCCACC), and introducing a gain-of-function mutation, R338L (FIX Padua). The efficiency of the published and the presently constructed cassettes was compared through in vivo screening. In addition, the regulatory elements that control the FIX gene expression in these cassettes were screened for liver-specific effectiveness. Among all the constructed cassettes, scAAV-Pre-hFIXco-SIH-R338L, which was the construct under the control of the prothrombin enhancer and prealbumin promoter, resulted in the highest level of coagulant activity, and the expression levels of two constructed cassettes (scAAV-Chi-hFIXco-SIH-R338L and scAAV-Pre-hFIXco-SIH-R338L) were also higher than that of the published cassette (scAAV-LP1-hFIXco-SJ). In summary, our strategies led to a substantial increase in hFIX expression at the protein level or a remarkably elevated coagulant activity. Thus, these reconstructs of hFIX with AAV vector may potentially contribute to the creation of an efficacious gene therapy of hemophilia B.

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Prevalence and determinations of physical inactivity among public hospital employees in Shanghai, China: a cross-sectional study
Xinjian Li,Minna Cheng,Hao Zhang,Ting Ke,Yisheng Chen
Front. Med.. 2015, 9 (1): 100-107.  
https://doi.org/10.1007/s11684-014-0372-9

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This study aims to explore the prevalence and determinations of physical inactivity among hospital employees in Shanghai, China. A cross-sectional study of 4612 employees aged 19 to 68 years was conducted through stratified cluster sampling from different classes of Shanghai hospitals in 2011. The total physical activity was evaluated using the metabolic equivalent according to the Global Physical Activity Questionnaire. Among the participants, 38.5%, 32.3%, and 64.6% of the employees are inactive at work, commuting, and taking leisure time, respectively. Up to 41.8% of the men and 37.8% of the women (P = 0.012) are physically inactive. When the age and educational level are adjusted, male doctors and medical technicians show a higher percentage of physical inactivity than male workers in logistics (P = 0.001). Among females, employees who are working in second- and third-class hospitals show a higher proportion of physical inactivity than those who are working in community health care centers. Logistic regression analyses show that the odds ratios (ORs) of leisure-time physical inactivity associated with the intensity of physical activity at work are 2.259, 2.897, and 4.266 for men (P<0.001) and 2.456, 3.259, and 3.587 for women (P<0.001), respectively. The time during commuting activities is significantly associated with leisure-time physical inactivity in either sex (OR= 2.116 for men and 2.173 for women, P<0.001). Hospital employees, particularly doctors and medical technicians, show a higher proportion of physical inactivity than other inhabitants in Shanghai. The time and intensity of activity at work and commuting are associated with leisure-time activities.

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CASE REPORT
A ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum
Eric C.H. Lai,Kam Man Chung,Stephanie H.Y. Lau,Wan Yee Lau
Front. Med.. 2015, 9 (1): 108-111.  
https://doi.org/10.1007/s11684-014-0344-0

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Hemoperitoneum is a rare and potentially life-threatening complication of GIST. We reported a 54-year-old man who developed disseminated intra-abdominal recurrence from a previously resected gastrointestinal stromal tumour (GIST) of the small bowel, and the patient presented with hemoperitoneum. Emergent debulking surgery was performed. A high dose imatinib was prescribed. Despite the presence of residual disease, the patient was well clinically 8 months after the operation. Even though, there is no evidence to support the routine use of debulking surgery in the management of GIST. In our patient, disease progression after second line targeted therapy and the absence of alternative treatment options for spontaneous rupture and hemoperitoneum prompted us to treat the patient aggressively. Resection of the ruptured GIST was carried out for control of bleeding and to prevent recurrent bleeding in this patient with good surgical risks. During the treatment decision-making, the patient’s general condition, the risk of surgery and the extent of dissemination were taken into consideration. In this patient who presented with spontaneous rupture of a small intestinal GIST, the novel use of targeted therapy and aggressive surgical treatment produced reasonably good survival outcome.

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A case of primary neuroendocrine breast carcinoma that responded to neo-adjuvant chemotherapy
Xiaolong Wei,Chunfa Chen,Didi Xi,Jinwen Bai,Wenhe Huang,Luoxiang Rong,Mingyao Wu,Guojun Zhang
Front. Med.. 2015, 9 (1): 112-116.  
https://doi.org/10.1007/s11684-014-0345-z

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Primary neuroendocrine breast carcinoma (NEBC) is a very rare type of breast cancer. Two characteristic biomarkers, namely, CgA and Syn, should be immunohistochemically detected to diagnose NEBC. In this study, a 43-year-old woman with a large mass of 8.3 cm × 2.9 cm in her right breast was reported. The patient was pathologically diagnosed with NEBC after specific markers, including CgA and Syn, as well as few differential markers, such as CK7, ER, PR, C-erbB-2, NSE, and E-cadherin, were immunohistochemically detected. The patient showed a remarkable response to four cycles of neo-adjuvant chemotherapy (partial response based on RECIST criteria) and sequentially underwent modified radical mastectomy. Moreover, the diagnosis and treatment of NEBC based on this case and available related literature were discussed.

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LETTER TO FRONTIERS OF MEDICINE
Insult of gastroesophageal reflux on airway: clinical significance of pharyngeal nozzle
Zhonggao Wang,Zhiwei Hu,Jimin Wu,Feng Ji,Hongtao Wang,Yungang Lai,Xiang Gao,Yachan Ning,Chengchao Zhang,Zhitong Li,Weitao Liang,Jianjun Liu
Front. Med.. 2015, 9 (1): 117-122.  
https://doi.org/10.1007/s11684-014-0343-1

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At the very time of global paying the highest attention to the worst insults of smoking as well as haze on the airway, everybody knows both are exogenous and noticeable. However, people mostly, including many medical personnel, do not know how badly the gastroesophageal reflux (GER) insults on our own airway. Symptoms of GER are commonly seen as heartburn and regurgitation, which can be mostly tolerated. However, when the up going gastric content reversely passes the esophagus and then the distal pharynx, where it appears a beak like stricture, serving as a nozzle, so as to produce numerous micro-particles and reach the oro-nasal cavity and also the airway causing allergic rhinitis and asthmatic attacks, even pulmonary parenchyma lesions. It will reduce life quality or even jeopardize life. The point that the endogenous insult appears in the respiratory system, but originates from the digestive tract is not well known and often undiagnosed and not correctly treated. The GER induced airway challenge is a treatable and preventive entity, as soon as a diagnosis is made, a good relief could be expected by means of life style adjustment, medicine, or fixation of the patulous cardia through radiofrequency or fundoplication. The author Dr. Zhonggao Wang had suffered it for long and symptoms disappeared for 8 years after anti-reflux surgery. Here is a presentation of Dr. Zhonggao Wang and his team’s work and would call attention to the public so as to recognize this relatively unknown entity — a treatable condition occurring from human itself, but not from outside surroundings as smoking or haze does.

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COMMENTARY
Essential training steps to achieving competency in the basic intraoperative transesophageal echocardiography examination for Chinese anesthesiologists
Yong G. Peng,Haibo Song,E. Wang,Weipeng Wang,Jin Liu
Front. Med.. 2015, 9 (1): 123-128.  
https://doi.org/10.1007/s11684-014-0366-7

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Guidelines for the intraoperative transesophageal echocardiography (TEE) examination have defined a detailed standard for medical professionals, particularly anesthesiologists, on how a TEE exam should proceed. Over the years, TEE has gained substantial popularity and emerged as a preferred monitoring modality to aid in perioperative management and decision making during hemodynamic instability situations or critical care settings. TEE training pathways and practice guidelines have been well established in western countries and many regions of the world. However, TEE training and practice information for anesthesiologists are lacking in China. As innovative technologies develop, other educational models have emerged to aid in obtaining competency in basic TEE exam. Hence, establishing a consensus on the ideal TEE training approach for anesthesiologists in China is urgently needed. Developing an effective curriculum that can be incorporated into an anesthesiology resident’s overall training is also necessary to provide knowledge and skills toward competency in basic TEE exam. With evolving medical system reforms and increasing demands for intraoperative hemodynamic monitoring to accommodate surgical innovations, anesthesiology professionals are increasingly obliged to perform intraoperative TEE exams in their current and future practices. To overcome obstacles and achieve significant progress in using the TEE modality to help in intraoperative management and surgical decision making, publishing basic TEE training guidelines for China’s anesthesiologists is an important endeavor.

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16 articles