Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2018, Volume 12 Issue 2
Reference values for immune recovery in patients after allo-SCT. Kinetics of recovered immune cells (monocyte, lymphocyte, B cells, T cells and their subsets) in event-free patients post HLA-identical and HLA-haploidentical SCT are provided. To provide reference values that can be used for all recipients, the effects of recipients’ age, gender, and [Detail] ...
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REVIEW
Gut microbial balance and liver transplantation: alteration, management, and prediction
Xinyao Tian, Zhe Yang, Fangzhou Luo, Shusen Zheng
Front. Med.. 2018, 12 (2): 123-129.  
https://doi.org/10.1007/s11684-017-0563-2

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Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia–reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

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Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia
Meng Dong, Jun Lin, Wonchung Lim, Wanzhu Jin, Hyuek Jong Lee
Front. Med.. 2018, 12 (2): 130-138.  
https://doi.org/10.1007/s11684-017-0555-2

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Brown adipose tissue (BAT) plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue (WAT), have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BAT activation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.

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Platelet-rich plasma: combinational treatment modalities for musculoskeletal conditions
Isabel Andia, Michele Abate
Front. Med.. 2018, 12 (2): 139-152.  
https://doi.org/10.1007/s11684-017-0551-6

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Current research on common musculoskeletal problems, including osteoarticular conditions, tendinopathies, and muscle injuries, focuses on regenerative translational medicine. Platelet-rich plasma therapies have emerged as a potential approach to enhance tissue repair and regeneration. Platelet-rich plasma application aims to provide supraphysiological concentrations of platelets and optionally leukocytes at injured/pathological tissues mimicking the initial stages of healing. However, the efficacy of platelet-rich plasma is controversial in chronic diseases because patients’ outcomes show partial improvements. Platelet-rich plasma can be customized to specific conditions by selecting the most appropriate formulation and timing for application or by combining platelet-rich plasma with synergistic or complementary treatments. To achieve this goal, researchers should identify and enhance the main mechanisms of healing. In this review, the interactions between platelet-rich plasma and healing mechanisms were addressed and research opportunities for customized treatment modalities were outlined. The development of combinational platelet-rich plasma treatments that can be used safely and effectively to manipulate healing mechanisms would be valuable and would provide insights into the processes involved in physiological healing and pathological failure.

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RESEARCH ARTICLE
Comparison of reference values for immune recovery between event-free patients receiving haploidentical allografts and those receiving human leukocyte antigen-matched sibling donor allografts
Xuying Pei, Xiangyu Zhao, Yu Wang, Lanping Xu, Xiaohui Zhang, Kaiyan Liu, Yingjun Chang, Xiaojun Huang
Front. Med.. 2018, 12 (2): 153-163.  
https://doi.org/10.1007/s11684-017-0548-1

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To establish optimal reference values for recovered immune cell subsets, we prospectively investigated post-transplant immune reconstitution (IR) in 144 patients who received allogeneic stem cell transplantation (allo-SCT) and without showing any of the following events: poor graft function, grades II?IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, or relapse or death in the first year after transplantation. IR was rapid in monocytes, intermediate in lymphocytes, CD3+ T cells, CD8+ T cells, and CD19+ B cells, and very slow in CD4+ T cells in the entire patient cohort. Immune recovery was generally faster under HLA-matched sibling donor transplantation than under haploidentical transplantation. Results suggest that patients with an IR comparable to the reference values display superior survival, and the levels of recovery in immune cells need not reach those in healthy donor in the first year after transplantation. We suggest that data from this recipient cohort should be used as reference values for post-transplant immune cell counts in patients receiving HSCT.

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Comparison in executive function in Chinese preterm and full-term infants at eight months
Yao Feng, Hong Zhou, Yan Zhang, Anthony Perkins, Yan Wang, Jing Sun
Front. Med.. 2018, 12 (2): 164-173.  
https://doi.org/10.1007/s11684-017-0540-9

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Executive function (EF) is increasingly recognized as being responsible for adverse developmental outcomes in preterm-born infants. Several perinatal factors may lead to poor EF development in infancy, and the deficits in EF can be identified in infants as young as eight months. A prospective cohort study was designed to study the EF in Chinese preterm infants and examine the relationship between EF in preterm infants and maternal factors during perinatal period. A total of 88 preterm infants and 88 full-term infants were followed from birth to eight months (corrected age). Cup Task and Planning Test was applied to assess the EF of infants, and the Bayley Scale of Infant Development (BSID-III) was used to evaluate cognitive (MDI) and motor abilities (PDI) of infants. In comparison with full-term infants, the preterm infants performed more poorly on all measures of EF including working memory, inhibition to prepotent responses, inhibition to distraction, and planning, and the differences remained after controlling the MDI and PDI. Anemia and selenium deficiency in mothers during pregnancy contributed to the differences in EF performance. However, maternal depression, hypertension, and diabetes during pregnancy were not related to the EF deficits in preterm infants. Future research should focus on the prevention of anemia and selenium deficiency during pregnancy and whether supplementing selenium in mothers during pregnancy can prevent further deterioration and the development of adverse outcomes of their offspring.

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Prevalence of vitamin D deficiency in girls with idiopathic central precocious puberty
Yue Zhao, Wenjun Long, Caiqi Du, Huanhuan Yang, Shimin Wu, Qin Ning, Xiaoping Luo
Front. Med.. 2018, 12 (2): 174-181.  
https://doi.org/10.1007/s11684-017-0544-5

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The relationship between vitamin D deficiency and idiopathic central precocious puberty (ICPP) has been recently documented. In this study, 280 girls diagnosed with ICPP and 188 normal puberty control girls of similar ages were enrolled and retrospectively studied. The ICPP group had significantly lower serum 25-hydroxyvitamin D (25[OH]D) levels than the control group. Furthermore, a nonlinear relationship was found between serum 25[OH]D and ICPP, and a cut-off point for serum 25[OH]D was found at 31.8 ng/ml for ICPP with and without adjusting the different confounding factors. Girls with serum 25[OH]D≥31.8 ng/ml had a lower odds ratio (unadjusted: OR 0.36, 95% CI 0.15 to 0.83, P <0.05; height and weight adjusted: OR 0.44, 95% CI 0.18 to 1.08, P = 0.072; BMI adjusted: OR 0.36, 95% CI 0.16 to 0.84, P <0.05). The ICPP subjects with 25[OH]D deficiency had a higher body mass index (BMI) than the subjects from the two other subgroups. Correlation analysis showed that vitamin D level is correlated with BMI and some metabolic parameters in the ICPP group. Our study suggested that vitamin D status may be associated with ICPP risk and may have a threshold effect on ICPP.

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Prevalence and drug resistance characteristics of carbapenem-resistant Enterobacteriaceae in Hangzhou, China
Yan Yang, Jian Chen, Di Lin, Xujian Xu, Jun Cheng, Changgui Sun
Front. Med.. 2018, 12 (2): 182-188.  
https://doi.org/10.1007/s11684-017-0529-4

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With the abuse of antimicrobial agents in developing countries, increasing number of carbapenem-resistant Enterobacteriaceae (CRE) attracted considerable public concern. A retrospective study was conducted based on 242 CRE strains from a tertiary hospital in Hangzhou, China to investigate prevalence and drug resistance characteristics of CRE in southeast China. Bacterial species were identified. Antimicrobial susceptibility was examined by broth microdilution method or epsilometer test. Resistant β-lactamase genes were identified by polymerase chain reaction and sequencing. Genotypes were investigated by phylogenetic analysis. Klebsiella pneumoniae and Escherichia coli were the most prevalent types of species, with occurrence in 71.9% and 21.9% of the strains, respectively. All strains exhibited high resistance (>70%) against β-lactam antibiotics, ciprofloxacin, trimethoprim–sulfamethoxazole, and nitrofurantoin but exhibited low resistance against tigecycline (0.8%) and minocycline (8.3%). A total of 123 strains harbored more than two kinds of β-lactamase genes. blaKPC-2, blaSHV-11, blaTEM-1, and blaCTX-M-14 were the predominant genotypes, with detection rates of 60.3%, 61.6%, 43.4%, and 16.5%, respectively, and were highly identical with reference sequences in different countries, indicating potential horizontal dissemination. IMP-4 was the most frequent class B metallo-lactamases in this study. In conclusion, continuous surveillance and effective prevention should be emphasized to reduce spread of CRE.

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Identification of surgical patients at high risk of OSAS using the Berlin Questionnaire to detect potential high risk of adverse respiratory events in post anesthesia care unit
Fei Liu, Li Liu, Fang Zheng, Xiangdong Tang, Yongxin Bao, Yunxia Zuo
Front. Med.. 2018, 12 (2): 189-195.  
https://doi.org/10.1007/s11684-017-0533-8

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Obstructive sleep apnea syndrome (OSAS) increases the risk of post-surgery complications. This study uses Berlin Questionnaire (BQ) to identify Chinese adult surgical patients who are at a high risk of OSAS and to determine if the BQ could be used to detect potential high risk of adverse respiratory events in the post anesthesia care unit (PACU). Results indicated that only 11.4% of the patients were considered at a high risk of OSAS. Age and body mass index are the key factors for the risk of OSAS prevalence in China and also gender specific. Furthermore, the incidence of adverse respiratory events in the PACU was higher in patients with high risk of OSAS than others (6.8% vs. 0.9%, P<0.001). They also stayed longer than others in the PACU (95±28 min vs. 62±19 min, P <0.001). Age, high risk for OSAS, and smoking were independent risk factors for the occurrence of adverse respiratory events in the PACU. The BQ may be adopted as a screening tool for anesthesiologists in China to identify patients who are at high risk of OSAS and determine the potential risk of developing postoperative respiratory complications in the PACU.

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Simultaneous detection and characterization of toxigenic Clostridium difficile directly from clinical stool specimens
Hanjiang Lai, Chen Huang, Jian Cai, Julian Ye, Jun She, Yi Zheng, Liqian Wang, Yelin Wei, Weijia Fang, Xianjun Wang, Yi-Wei Tang, Yun Luo, Dazhi Jin
Front. Med.. 2018, 12 (2): 196-205.  
https://doi.org/10.1007/s11684-017-0560-5

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We employed a multiplex polymerase chain reaction (PCR) coupled with capillary electrophoresis (mPCR-CE) targeting six Clostridium difficile genes, including tpi, tcdA, tcdB, cdtA, cdtB, and a deletion in tcdC for simultaneous detection and characterization of toxigenic C. difficile directly from fecal specimens. The mPCR-CE had a limit of detection of 10 colony-forming units per reaction with no cross-reactions with other related bacterial genes. Clinical validation was performed on 354 consecutively collected stool specimens from patients with suspected C. difficile infection and 45 isolates. The results were compared with a reference standard combined with BD MAX Cdiff, real-time cell analysis assay (RTCA), and mPCR-CE. The toxigenic C. difficile species were detected in 36 isolates and 45 stool specimens by the mPCR-CE, which provided a positive rate of 20.3% (81/399). The mPCR-CE had a specificity of 97.2% and a sensitivity of 96.0%, which was higher than RTCA (x2 = 5.67, P = 0.017) but lower than BD MAX Cdiff (P = 0.245). Among the 45 strains, 44 (97.8%) were determined as non-ribotype 027 by the mPCR-CE, which was fully agreed with PCR ribotyping. Even though ribotypes 017 (n = 8, 17.8%), 001 (n = 6, 13.3%), and 012 (n = 7, 15.6%) were predominant in this region, ribotype 027 was an important genotype monitored routinely. The mPCR-CE provided an alternative diagnosis tool for the simultaneous detection of toxigenic C. difficile in stool and potentially differentiated between RT027 and non-RT027.

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Multistage analysis method for detection of effective herb prescription from clinical data
Kuo Yang, Runshun Zhang, Liyun He, Yubing Li, Wenwen Liu, Changhe Yu, Yanhong Zhang, Xinlong Li, Yan Liu, Weiming Xu, Xuezhong Zhou, Baoyan Liu
Front. Med.. 2018, 12 (2): 206-217.  
https://doi.org/10.1007/s11684-017-0525-8

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Determining effective traditional Chinese medicine (TCM) treatments for specific disease conditions or particular patient groups is a difficult issue that necessitates investigation because of the complicated personalized manifestations in real-world patients and the individualized combination therapies prescribed in clinical settings. In this study, a multistage analysis method that integrates propensity case matching, complex network analysis, and herb set enrichment analysis was proposed to identify effective herb prescriptions for particular diseases (e.g., insomnia). First, propensity case matching was applied to match clinical cases. Then, core network extraction and herb set enrichment were combined to detect core effective herb prescriptions. Effectiveness-based mutual information was used to detect strong herb–symptom relationships. This method was applied on a TCM clinical data set with 955 patients collected from well-designed observational studies. Results revealed that groups of herb prescriptions with higher effectiveness rates (76.9% vs. 42.8% for matched samples; 94.2% vs. 84.9% for all samples) compared with the original prescriptions were found. Particular patient groups with symptom manifestations were also identified to help investigate the indications of the effective herb prescriptions.

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Qualitative analysis of direction of public hospital reforms in China
Dahai Zhao, Zhiruo Zhang
Front. Med.. 2018, 12 (2): 218-223.  
https://doi.org/10.1007/s11684-017-0534-7

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Reforms in public hospitals are among the most important improvements in China’s health care system over the last two decades. However, the reforms that should be implemented in public hospitals are unclear. Thus, a feasible direction of reforms in Chinese public hospitals is suggested and reliable policy suggestions are provided for the government to reform public hospitals. The data used in this study were mainly derived from a qualitative study. Focus group discussions and in-depth interviews were conducted in Shanghai, Guangdong, and Gansu between May and December 2014. Government funding accounted for approximately eight percent of the total annual revenue of public hospitals in China, and the insufficient government subsidy considerably affects the operation mechanism of public hospitals. However, solely increasing this subsidy cannot address the inappropriate incentives of public hospitals in China. The most crucial step in setting the direction of reforms in public hospitals in China is transforming inappropriate incentives by implementing a new evaluation index system for directors and physicians in public hospitals.

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CASE REPORT
Lung transplantation for bronchiolitis obliterans syndrome after allogenic hematopoietic stem cell transplantation
Fei Gao, Jingyu Chen, Dong Wei, Bo Wu, Min Zhou
Front. Med.. 2018, 12 (2): 224-228.  
https://doi.org/10.1007/s11684-017-0538-3

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Bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) is a major cause of morbidity and mortality with limited treatment options. Lung transplantation (LTX) has been rarely reported as a treatment option for selected HSCT recipients with this problem. In the present study, we reported six patients who underwent LTX due to BOS after HSCT (two females, four males) from January 2012 to December 2014 in our center. The median time from HSCT to diagnosis of BOS was 2.5 years (ranging from 1 to 5 years). At a median time of 4 years (ranging from 2 to 5 years) after diagnosis of BOS, four patients received bilateral sequential LTX, and two patients received single LTX. One of the recipients suffered from mild acute rejection after LTX, another suffered from primary lung graft dysfunction on post-operation day 2, and three experienced fungal infections. The median time for follow-up after LTX was 19.5 months (ranging from 12 to 39 months). At present, all patients are alive with good functional capacity and no relapse of BOS and hematologic malignancy conditions. Patients who received bilateral LTX have better pulmonary functions than patients who received single LTX.

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COMMENTARY
Molecular classification and precision therapy of cancer: immune checkpoint inhibitors
Yingyan Yu
Front. Med.. 2018, 12 (2): 229-235.  
https://doi.org/10.1007/s11684-017-0581-0

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On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as “genetic interpreters” or “genetic translators” and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.

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Carcinogens that induce the A:T>T:A nucleotide substitutions in the genome
Guangbiao Zhou, Xinchun Zhao
Front. Med.. 2018, 12 (2): 236-238.  
https://doi.org/10.1007/s11684-017-0611-y

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Recently, Ng et al. reported that the A:T>T:A substitutions, proposed to be a signature of aristolochic acid (AA) exposure, were detected in 76/98 (78%) of patients with hepatocellular carcinoma (HCC) from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients’ exposure history is the key to determine the “culprit” of the A:T>T:A mutations. Apparently, without estimation of the patients’ exposure history, the conclusion of Ng et al. is unpersuasive and misleading.

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14 articles