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1.  Urine sTREM-1 may be a valuable biomarker in diagnosis and prognosis of sepsis-associated acute kidney injury 
Critical Care  2015;19(1):281.
Urine soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) has been reported in sepsis diagnosis and prediction of sepsis-associated acute kidney injury (AKI). However, the mechanisms of the role of sTREM-1 for AKI remain unclear. It may be that topical inflammatory response of kidney, not just systemic inflammation, contributes to the elevated secretion of urine sTREM-1 in the process of sepsis-associated AKI. To further evaluate the role of sTREM-1 in this process, a larger-cohort multicenter study and the relevant basic research should be performed to reveal the diagnostic value and mechanism of sTREM-1 during the sepsis-associated AKI process. If successful, then urine sTREM-1 would be a good marker for sepsis and its associated AKI and could contribute to non-invasive diagnosis and monitoring in the clinical setting. Additionally, owing to the complexity of the pathogenesis of sepsis, it is necessary to combine some biomarkers to improve diagnostic performance in the diagnosis of sepsis-associated AKI rather than relying on a single marker.
PMCID: PMC4501200  PMID: 26169055
2.  Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(6):e0129450.
Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05–3.30) using a random-effects model (I2 = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73–0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67–0.82) and 0.64 (95% CI, 0.52–0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35–3.95) using a fixed-effects model (I2 = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75–0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58–0.82) and 0.77 (95% CI, 0.55–0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.
PMCID: PMC4468164  PMID: 26076027
3.  Dynamic Changes in Amino Acid Concentration Profiles in Patients with Sepsis 
PLoS ONE  2015;10(4):e0121933.
The goal of this work was to explore the dynamic concentration profiles of 42 amino acids and the significance of these profiles in relation to sepsis, with the aim of providing guidance for clinical therapies.
Thirty-five critically ill patients with sepsis were included. These patients were further divided into sepsis (12 cases) and severe sepsis (23 cases) groups or survivor (20 cases) and non-survivor (15 cases) groups. Serum samples from the patients were collected on days 1, 3, 5, 7, 10, and 14 following intensive care unit (ICU) admission, and the serum concentrations of 42 amino acids were measured.
The metabolic spectrum of the amino acids changed dramatically in patients with sepsis. As the disease progressed further or with poor prognosis, the levels of the different amino acids gradually increased, decreased, or fluctuated over time. The concentrations of sulfur-containing amino acids (SAAs), especially taurine, decreased significantly as the severity of sepsis worsened or with poor prognosis of the patient. The serum concentrations of SAAs, especially taurine, exhibited weak negative correlations with the Sequential Organ Failure Assessment (SOFA) (r=-0.319) and Acute Physiology and Chronic Health Evaluation (APACHE) II (r=-0.325) scores. The areas under the receiver operating characteristic curves of cystine, taurine, and SAA levels and the SOFA and APACHE II scores, which denoted disease prognosis, were 0.623, 0.674, 0.678, 0.86, and 0.857, respectively.
Critically ill patients with disorders of amino acid metabolism, especially of SAAs such as cystine and taurine, may provide an indicator of the need for the nutritional support of sepsis in the clinic.
Trial Registration identifier NCT01818830.
PMCID: PMC4388841  PMID: 25849571
4.  Tracheobronchopathia osteochondroplastica: Case report and literature review 
Tracheobronchopathia osteochondroplastica (TPO) is a rare disorder characterized as multiple osseous or cartilaginous nodules in the submucosa of trachea and main bronchi. TPO remains an under recognized entity due to lack of awareness. Four cases of TPO are reported in this review as well as various facets of TPO description.
PMCID: PMC4501471
Tracheobronchopathia osteochondroplastica; Tracheal stenosis; Tracheal disease; Ossification
5.  Prognostic value of different scoring models in patients with multiple organ dysfunction syndrome associated with acute COPD exacerbation 
Journal of Thoracic Disease  2015;7(3):329-336.
Background and objective
Chronic obstructive pulmonary disease (COPD) represents an increasing healthcare concern as a leading cause of morbidity and mortality worldwide. Our objective was to predict the outcome of COPD patients associated with multiple organ dysfunction syndrome (MODS) by scoring models.
A retrospective study was performed on severe COPD patients within 24 hours of the onset of MODS. The Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, Multiple Organ Dysfunction Score (MODS), Simplified Acute Physiology Score II (SAPS II), and Sepsis-related Organ Failure Assessment (SOFA) scores were calculated for patients.
A total of 153 elderly patients were recruited. Compared to 30-day survivors, the number of failing organs and all of the scoring models were significantly higher in 30-day non-survivors. The SOFA showed the highest sensitivity and area under the curve (AUC) for predicting the prognosis of patients with MODS induced by acute exacerbation of COPD. The results of logistic regression indicated that factors that were correlated with the prognosis of COPD included the exacerbation history, SOFA score, number of failing organs, and duration of ICU stay. The value of exacerbation frequency for predicting the outcome of COPD was excellent (AUC: 0.892), with a sensitivity of 0.851 and a specificity of 0.797.
The SOFA score, determined at the onset of MODS in elderly patients with COPD, was a reliable predictor of the prognosis. The exacerbation frequency, number of failing organs, and the SOFA score were risk factors of a poor prognosis, and the exacerbation frequency could also effectively predict the outcome of COPD.
PMCID: PMC4387415  PMID: 25922710
Acute exacerbation (AE); chronic obstructive pulmonary disease (COPD); multiple organ dysfunction syndrome (MODS); prognosis
6.  Serum miR-122 correlates with short-term mortality in sepsis patients 
Critical Care  2014;18(6):704.
PMCID: PMC4262971  PMID: 25672224
7.  Discrimination of sepsis stage metabolic profiles with an LC/MS-MS-based metabolomics approach 
BMJ Open Respiratory Research  2014;1(1):e000056.
To identify metabolic biomarkers that can be used to differentiate sepsis from systemic inflammatory response syndrome (SIRS), assess severity and predict outcomes.
65 patients were involved in this study, including 35 patients with sepsis, 15 patients with SIRS and 15 normal patients. Small metabolites that were present in patient serum samples were measured by liquid chromatography mass spectrometry techniques and analysed using multivariate statistical methods.
The metabolic profiling of normal patients and patients with SIRS or sepsis was markedly different. A significant decrease in the levels of lactitol dehydrate and S-phenyl-d-cysteine and an increase in the levels of S-(3-methylbutanoyl)-dihydrolipoamide-E and N-nonanoyl glycine were observed in patients with sepsis in comparison to patients with SIRS (p<0.05). Patients with severe sepsis and septic shock displayed lower levels of glyceryl-phosphoryl-ethanolamine, Ne, Ne dimethyllysine, phenylacetamide and d-cysteine (p<0.05) in their sera. The profiles of patients with sepsis 48 h before death illustrated an obvious state of metabolic disorder, such that S-(3-methylbutanoyl)-dihydrolipoamide-E, phosphatidylglycerol (22:2 (13Z, 16Z)/0:0), glycerophosphocholine and S-succinyl glutathione were significantly decreased (p<0.05). The receiver operating characteristic curve of the differential expression of these metabolites was also performed.
The body produces significant evidence of metabolic disorder during SIRS or sepsis. Seven metabolites may potentially be used to diagnose sepsis.
Trial registration number identifier NCT01649440.
PMCID: PMC4265126  PMID: 25553245
Respiratory Infection
8.  A Multi-Center, Cross-Sectional Study on the Burden of Infectious Keratitis in China 
PLoS ONE  2014;9(12):e113843.
To understand the prevalence and demographic characteristics of infectious keratitis and infectious corneal blindness.
A multi-center, population-based cross-sectional study was conducted from January 1 to August 31, 2010. A total of 191,242 individuals of all age groups from 10 geographically representative provinces were sampled using stratified, multi-stage, random and systematic sampling procedures. A majority, 168,673 (88.2%), of those sampled participated in the study. The examination protocol included a structured interview, visual acuity testing, an external eye examination, and an anterior segment examination using a slit lamp. The causes and sequelae of corneal disease were identified using uniform customized protocols. Blindness in one eye caused by infectious keratitis was defined as infectious corneal blindness.
The prevalence of past and active infectious keratitis was 0.192% (95% confidence interval [CI], 0.171–0.213%), and the prevalence of viral, bacterial, and fungal keratitis was 0.11%, 0.075%, and 0.007%, respectively. There were 138 cases of infectious corneal blindness in at least one eye in the study population (prevalence of 0.082% [95%CI, 0.068%–0.095%]). Statistical analysis suggested that ocular trauma, alcoholic consumption, low socioeconomic levels, advanced age, and poor education were risk factors for infectious corneal blindness.
Infectious keratitis is the leading cause of corneal blindness in China. Eye care strategies should focus on the prevention and rehabilitation of infectious corneal blindness.
PMCID: PMC4250054  PMID: 25438169
9.  ROCK Inhibitor Y-27632 Increases the Cloning Efficiency of Limbal Stem/Progenitor Cells by Improving Their Adherence and ROS-Scavenging Capacity 
Rho-associated coiled-coil kinase (ROCK) inhibitor Y-27632 has been shown to increase proliferative capacity and even immortalize primary keratinocytes. Here, we demonstrate that rabbit primary limbal epithelial cells (LECs) treated with Y-27632 also exhibited improved colony-forming efficiency by enhancing the expansion of the stem/progenitor cells. Moreover, Y-27632 treatment improved the rapid adherence of limbal stem/progenitor cells in the initial inoculation of primary cells. In addition, Y-27632 treatment elevated the intracellular glutathione level and decreased cellular reactive oxygen species (ROS) accumulation during the expansion of LECs. Therefore, ROCK inhibitor Y-27632 increased the cloning efficiency of rabbit limbal stem/progenitor cells by improving their adherence and ROS scavenging capacity.
PMCID: PMC3662381  PMID: 23151007
10.  Laboratory analyses of two explanted hydrophobic acrylic intraocular lenses 
Indian Journal of Ophthalmology  2014;62(6):737-739.
Two three-piece hydrophobic acrylic intraocular lenses (IOLs) were explanted from two patients at 7 and 9 years, respectively, after implantation, because of poor fundus visualisation and/or a clinically significant decrease in visual acuity related to their opacified IOLs. In addition to light microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy, confocal laser scanning microscopy was used for the first time to observe the explanted IOLs. The clinical aspect seemed to correspond to the phenomenon of surface light scattering, while laboratory analyses showed dense glistenings in the central layer of the IOL optic, which had no change next to the surface. Further studies on these phenomena are needed.
PMCID: PMC4131335  PMID: 25005210
Glistenings; hydrophobic acrylic; intraocular lens
11.  Diagnostic Value of Dynamics Serum sCD163, sTREM-1, PCT, and CRP in Differentiating Sepsis, Severity Assessment, and Prognostic Prediction 
Mediators of Inflammation  2013;2013:969875.
Objective. To describe the dynamics changes of sCD163, soluble serum triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) during the course of sepsis, as well as their outcome prediction. Patients and Methods. An SIRS group (30 cases) and a sepsis group (100 cases) were involved in this study. Based on a 28-day survival, the sepsis was further divided into the survivors' and nonsurvivors' groups. Serum sTREM-1, sCD163, PCT, CRP, and WBC counts were tested on days 1, 3, 5, 7, 10, and 14. Results. On the ICU admission, the sepsis group displayed higher levels of sTREM-1, sCD163, PCT, and CRP than the SIRS group (P < 0.05). Although PCT and sTREM-1 are good markers to identify severity, sTREM-1 is more reliable, which proved to be a risk factor related to sepsis. During a 14-day observation, sCD163, sTREM-1, PCT, and SOFA scores continued to climb among nonsurvivors, while their WBC and CRP went down. Both sCD163 and SOFA scores are risk factors impacting the survival time. Conclusion. With regard to sepsis diagnosis and severity, sTREM-1 is more ideal and constitutes a risk factor. sCD163 is of a positive value in dynamic prognostic assessment and may be taken as a survival-impacting risk factor.
PMCID: PMC3713373  PMID: 23935252
12.  Identification of Novel Biomarkers for Sepsis Prognosis via Urinary Proteomic Analysis Using iTRAQ Labeling and 2D-LC-MS/MS 
PLoS ONE  2013;8(1):e54237.
Sepsis is the major cause of death for critically ill patients. Recent progress in proteomics permits a thorough characterization of the mechanisms associated with critical illness. The purpose of this study was to screen potential biomarkers for early prognostic assessment of patients with sepsis.
For the discovery stage, 30 sepsis patients with different prognoses were selected. Urinary proteins were identified using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with LC-MS/MS. Mass spec instrument analysis were performed with Mascot software and the International Protein Index (IPI); bioinformatic analyses were used by the algorithm of set and the Gene Ontology (GO) Database. For the verification stage, the study involved another 54 sepsis-hospitalized patients, with equal numbers of patients in survivor and non-survivor groups based on 28-day survival. Differentially expressed proteins were verified by Western Blot.
A total of 232 unique proteins were identified. Proteins that were differentially expressed were further analyzed based on the pathophysiology of sepsis and biomathematics. For sepsis prognosis, five proteins were significantly up-regulated: selenium binding protein-1, heparan sulfate proteoglycan-2, alpha-1-B glycoprotein, haptoglobin, and lipocalin; two proteins were significantly down-regulated: lysosome-associated membrane proteins-1 and dipeptidyl peptidase-4. Based on gene ontology clustering, these proteins were associated with the biological processes of lipid homeostasis, cartilage development, iron ion transport, and certain metabolic processes. Urinary LAMP-1 was down-regulated, consistent with the Western Blot validation.
This study provides the proteomic analysis of urine to identify prognostic biomarkers of sepsis. The seven identified proteins provide insight into the mechanism of sepsis. Low urinary LAMP-1 levels may be useful for early prognostic assessment of sepsis.
Trial Registration NCT01493492
PMCID: PMC3553154  PMID: 23372690
13.  Mutation analysis of paired box 6 gene in inherited aniridia in northern China 
Molecular Vision  2013;19:1169-1177.
Aniridia is phenotypically and genetically heterogeneous. This study is to summarize the phenotypes and identify the underlying genetic cause of the paired box 6 (PAX6) gene responsible for aniridia in two three-generation Chinese families in northern China.
A detailed family history and clinical data were collected from patients during an ophthalmologic examination. All exons and flanking intronic sequences of the PAX6 gene were amplified with PCR and screened for mutation with direct DNA sequencing. Haplotyping was used to confirm the mutation sequence. Real-time PCR was used to determine the PAX6 messenger ribonucleic acid(mRNA) level in patients with aniridia and in unaffected family members.
The probands and other patients in the two families were affected with aniridia accompanied with or without congenital cataract. A heterozygous PAX6 mutation in exon 5 (c.112delC, p.Arg38GlyfsX16) was identified in FAMILY-1, which was predicted to generate a frameshift and created a premature termination codon. A heterozygous PAX6 mutation in exon 7 (c.362C>T, p.Ser121Leu) was identified in FAMILY-2. Each mutation cosegregated with the affected individuals in the family and did not exist in unaffected family members and 200 unrelated normal controls. The PAX6 messenger ribonucleic acid level was about 50% lower in patients with aniridia than in unaffected family members in FAMILY-1.
The deletion mutation (c.112delC) in the PAX6 gene was first identified in a Chinese family with aniridia, congenital progressive cataract, developmental delay, or the absence of ulna. The mutation (c.362C>T, p.Ser121Leu) in the PAX6 gene was first identified in a patient with aniridia with congenital ptosis. We summarized the variable phenotypes among the patients, which expanded the phenotypic spectrum of aniridia in a different ethnic background.
PMCID: PMC3669533  PMID: 23734086
14.  Diagnostic value of urine sCD163 levels for sepsis and relevant acute kidney injury: a prospective study 
BMC Nephrology  2012;13:123.
Sepsis is a common syndrome in critically ill patients and easily leads to the occurrence of acute kidney injury (AKI), with high mortality rates. This study aimed to investigate the diagnostic value of urine soluble CD163 (sCD163) for identification of sepsis, severity of sepsis, and for secondary AKI, and to assess the patients’ prognosis.
We enrolled 20 cases with systemic inflammatory response syndrome (SIRS), 40 cases with sepsis (further divided into 17 sepsis cases and 23 severe sepsis cases) admitted to the intensive care unit (ICU), and 20 control cases. Results for urine sCD163 were recorded on the day of admission to the ICU, and AKI occurrence was noted.
On the day of ICU admission, the sepsis group exhibited higher levels of urine sCD163 (74.8 ng/ml; range: 47.9-148.3 ng/ml) compared with those in the SIRS group (31.9 ng/ml; 16.8-48.0, P < 0.001). The area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.72-0.94, P < 0.001) the sensitivity was 0.83, and the specificity was 0.75 (based on a cut-off point of 43.0 ng/ml). Moreover, the severe sepsis group appeared to have a higher level of sCD163 compared with that in the sepsis group (76.2; 47.2-167.5 ng/ml vs. 74.2; 46.2-131.6 ng/ml), but this was not significant. For 15 patients with AKI, urine sCD163 levels at AKI diagnosis were significantly higher than those of the remaining 35 sepsis patients upon ICU admission (121.0; 74.6-299.1 ng/ml vs. 61.8; 42.8-128.3 ng/ml, P = 0.049). The AUC for urine sCD163 was 0.688 (95% CI: 0.51-0.87, P = 0.049). Sepsis patients with a poor prognosis showed a higher urine sCD163 level at ICU admission (98.6; 50.3-275.6 ng/ml vs. 68.0; 44.8-114.5 ng/ml), but this was not significant. Patients with AKI with a poor prognosis had higher sCD163 levels than those in patients with a better prognosis (205.9; 38.6-766.0 ng/ml vs. 80.9; 74.9-141.0 ng/ml), but this was not significant.
This study shows, for the first time, the potential value of urine sCD163 levels for identifying sepsis and diagnosing AKI, as well as for assessment of patients’ prognosis.
Trial Registration
PMCID: PMC3506529  PMID: 23013330
Urine; Soluble CD163 (sCD163); Sepsis; Systemic inflammatory response syndrome (SIRS); Prognosis; Acute kidney injury (AKI)
15.  Value of soluble TREM-1, procalcitonin, and C-reactive protein serum levels as biomarkers for detecting bacteremia among sepsis patients with new fever in intensive care units: a prospective cohort study 
BMC Infectious Diseases  2012;12:157.
The purpose of this study was to explore the diagnostic value of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for differentiating sepsis from SIRS, identifying new fever caused by bacteremia, and assessing prognosis when new fever occurred.
We enrolled 144 intensive care unit (ICU) patients: 60 with systemic inflammatory response syndrome (SIRS) and 84 with sepsis complicated by new fever at more than 48 h after ICU admission. Serum sTREM-1, PCT, and CRP levels were measured on the day of admission and at the occurrence of new fever (>38.3°C) during hospitalization. Based on the blood culture results, the patients were divided into a blood culture-positive bacteremia group (33 patients) and blood culture-negative group (51 patients). Based on 28-day survival, all patients, both blood culture-positive and -negative, were further divided into survivor and nonsurvivor groups.
On ICU day 1, the sepsis group had higher serum sTREM-1, PCT, and CRP levels compared with the SIRS group (P <0.05). The areas under the curve (AUC) for these indicators were 0.868 (95% CI, 0.798–0.938), 0.729 (95% CI, 0.637–0.821), and 0.679 (95% CI, 0.578–0.771), respectively. With 108.9 pg/ml as the cut-off point for serum sTREM-1, sensitivity was 0.83 and specificity was 0.81. There was no statistically significant difference in serum sTREM-1 or PCT levels between the blood culture-positive and -negative bacteremia groups with ICU-acquired new fever. However, the nonsurvivors in the blood culture-positive bacteremia group had higher levels of serum sTREM-1 and PCT (P <0.05), with a prognostic AUC for serum sTREM-1 of 0.868 (95% CI, 0.740–0.997).
Serum sTREM-1, PCT, and CRP levels each have a role in the early diagnosis of sepsis. Serum sTREM-1, with the highest sensitivity and specificity of all indicators studied, is especially notable. sTREM-1, PCT, and CRP levels are of no use in determining new fever caused by bacteremia in ICU patients, but sTREM-1 levels reflect the prognosis of bacteremia.
Trial registration identifier NCT01410578
PMCID: PMC3426475  PMID: 22809118
Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1); Fever; Sepsis; Bacteremia; Diagnosis; Prognosis
16.  Serum MicroRNA Signatures Identified by Solexa Sequencing Predict Sepsis Patients’ Mortality: A Prospective Observational Study 
PLoS ONE  2012;7(6):e38885.
Sepsis is the leading cause of death in Intensive Care Units. Novel sepsis biomarkers and targets for treatment are needed to improve mortality from sepsis. MicroRNAs (miRNAs) have recently been used as finger prints for sepsis, and our goal in this prospective study was to investigate if serum miRNAs identified in genome-wide scans could predict sepsis mortality.
Methodology/Principal Findings
We enrolled 214 sepsis patients (117 survivors and 97 non-survivors based on 28-day mortality). Solexa sequencing followed by quantitative reverse transcriptase polymerase chain reaction assays was used to test for differences in the levels of miRNAs between survivors and non-survivors. miR-223, miR-15a, miR-16, miR-122, miR-193*, and miR-483-5p were significantly differentially expressed. Receiver operating characteristic curves were generated and the areas under the curve (AUC) for these six miRNAs for predicting sepsis mortality ranged from 0.610 (95%CI: 0.523–0.697) to 0.790 (95%CI: 0.719–0.861). Logistic regression analysis showed that sepsis stage, Sequential Organ Failure Assessment scores, Acute Physiology and Chronic Health Evaluation II scores, miR-15a, miR-16, miR-193b*, and miR-483-5p were associated with death from sepsis. An analysis was done using these seven variables combined. The AUC for these combined variables’ predictive probability was 0.953 (95% CI: 0.923–0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712–0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672–0.832), and procalcitonin levels (0.689; 95% CI: 0.611–0.784). With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%. Additionally, miR-193b* had the highest odds ratio for sepsis mortality of 9.23 (95% CI: 1.20–71.16).
Six serum miRNA’s were identified as prognostic predictors for sepsis patients.
Trial Registration NCT01207531
PMCID: PMC3376145  PMID: 22719975
17.  Histological Evaluation of Corneal Scar Formation in Pseudophakic Bullous Keratopathy 
PLoS ONE  2012;7(6):e39201.
To evaluate histological changes in the corneal stroma in pseudophakic bullous keratopathy.
Twenty-eight patients (28 eyes) with pseudophakic bullous keratopathy underwent therapeutic penetrating keratoplasty at Shandong Eye Institute between January 2006 and November 2011. The patients were divided into two groups according to the duration of bullous keratopathy (<1.0 year group or >1.0 year group), and three buttons from enucleated eyes with choroidal melanoma served as a control. In vivo confocal microscopy examination, hematoxylin–eosin, Masson's trichrome stain and Van Gieson staining were used for microscopic examination. The histological evaluation and scoring of the buttons for morphological changes, including the degree of stromal scars, neovascularization and inflammatory cells within the corneal buttons, were compared. To study the underlying mechanism, connective tissue growth factor (CTGF) and TGF-β immunohistochemistry were performed.
Confocal microscopy examination and histological evaluation and scoring of the buttons showed that compared with the <1.0 year group, stromal scars, neovascularization and inflammatory cells were more severe in the >1.0 year group (P<0.05). There was an increase in CTGF- and TGF-β1-positive stromal cells in the >1.0 year group.
During the progression of pseudophakic bullous keratopathy, stromal scars occurred more often in the patients that had a longer duration of disease. Cytokines such as CTGF and TGF-β1 may play a role in this pathological process and deserve further investigation.
PMCID: PMC3375240  PMID: 22720074
18.  Inhibition of VEGF expression and corneal neovascularization by shRNA targeting HIF-1α in a mouse model of closed eye contact lens wear 
Molecular Vision  2012;18:864-873.
Inappropriate contact lens (CL) use and care often lead to corneal neovascularization (corneal NV). We used mouse eyes which wore CL as the animal model to assess the reason for corneal NV with CL wear. The similar and overlapping activity of vascular endothelial growth factor (VEGF) and the potent angiogenic hypoxia-inducible factor 1α (HIF-1α) called for a study of the temporal relationship in the expression of these two autocoids. We determined the time dependent expression of HIF-1α and correlated it to that of VEGF expression in the mouse model of closed eye with CL wear.
Mouse eyes were fitted with CL followed by a silk suture tarsorrhaphy. The anterior surface was analyzed at 4, 7, and 10 days after tarsorrhaphy by slit lamp and corneal NV. HIF-1α and VEGF levels were measured by reverse transcription PCR, western blotting and immunofluorescence with specific primers and antibodies. We used shRNA targeting HIF-1α to substantiate the link between HIF-1α, VEGF expression, and angiogenesis in the CL wear model.
Corneal NV scores increased in a time dependent manner in the model of closed eye CL induced hypoxic injury. Corneal epithelial HIF-1α and VEGF expression increased in a time dependent manner. The prolonged hypoxic state brought by closed eye CL wear induced a time dependent neovascular response which was significantly attenuated by HIF-1α specific shRNA but not by nonspecific shRNA. Both HIF-1α and VEGF levels were reduced significantly in corneal homogenates from eyes treated with the HIF-1α specific shRNA.
The present study documented the increased expression of HIF-1α in the corneal epithelium during CL wear. It also demonstrated the presence of VEGF in the corneal epithelium and its increased expression in this model. Altogether, the results of this study raised the possibility of interaction between HIF-1α and VEGF, in mediating the neovascularization response induced by the prolonged hypoxic state brought about by closed eye CL wear. The results strongly implicated corneal HIF-1α as a component of the inflammatory and neovascular cascade initiated by hypoxic and further suggested that HIF-1α was a proximal regulator of VEGF expression in this model.
PMCID: PMC3327437  PMID: 22511848
19.  Dynamic changes of serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflect sepsis severity and can predict prognosis: a prospective study 
We examined the utility of serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) for the diagnoses, severity assessments, and predicting the prognoses of patients with sepsis and compared sTREM-1 values with those of C-reactive protein (CRP) and procalcitonin (PCT).
Fifty-two patients with sepsis were included: 15 sepsis cases and 37 severe sepsis cases (severe sepsis + septic shock). Serum levels of sTREM-1, CRP, and PCT were determined on days 1, 3, 5, 7, 10, and 14 after admission to an ICU.
Serum sTREM-1 levels of patients with severe sepsis were significantly higher than for those with sepsis on day 1 (240.6 pg/ml vs. 118.3 pg/ml; P < 0.01), but CRP and PCT levels were not significantly different between the two groups. The area under an ROC curve for sTREM-1 for severe sepsis patients was 0.823 (95% confidence interval: 0.690-0.957). Using 222.5 pg/ml of sTREM-1 as the cut-off value, the sensitivity was 59.5%, the specificity was 93.3%, the positive predictive value was 95.6%, the negative predictive value was 48.3%, the positive likelihood ratio was 8.92, and the negative likelihood ratio was 0.434. Based on 28-day survivals, sTREM-1 levels in the surviving group showed a tendency to decrease over time, while they tended to gradually increase in the non-surviving group. sTREM-1 levels in the non-surviving group were higher than those in the surviving group at all time points, whereas CRP and PCT levels showed a tendency to decrease over time in both groups. sTREM-1 levels and Sequential Organ Failure Assessment (SOFA) scores were positively correlated (r = 0.443; P < 0.001), and this correlation coefficient was greater than the correlation coefficients for both CRP and PCT.
Serum sTREM-1 levels reflected the severity of sepsis more accurately than those of CRP and PCT and were more sensitive for dynamic evaluations of sepsis prognosis.
Trial Registration
Current controlled trials ChiCTR-OCH-09000745
PMCID: PMC3056794  PMID: 21356122
20.  Activation of focal adhesion kinase enhances the adhesion of Fusarium solani to human corneal epithelial cells via the tyrosine-specific protein kinase signaling pathway 
Molecular Vision  2011;17:638-646.
To determine the role of the integrin-FAK signaling pathway triggered by the adherence of F. solani to human corneal epithelial cells (HCECs).
After pretreatment with/without genistein, HCECs were incubated with F. solani spores at different times (0–24 h). Cell adhesion assays were performed by optical microscopy. Changes of the ultrastructure were observed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The expression of F-actin and Paxillin (PAX) were detected by immunofluorescence and western blotting to detect the expression of these key proteins with/without genistein treatment.
Cell adhesion assays showed that the number of adhered spores began to rise at 6 h after incubation and peaked at 8 h. SEM and TEM showed that the HCECs exhibited a marked morphological alteration induced by the attachment and entry of the spores. The expression of PAX increased, while the expression of F-actin decreased by stimulation with F. solani. The interaction of F. solani with HCECs causes actin rearrangement in HCECs. Genistein strongly inhibited FAK phosphorylation and the activation of the downstream protein (PAX). F. solani-induced enhancement of cell adhesion ability was inhibited along with the inhibition of FAK phosphorylation.
Our results suggest that the integrin-FAK signaling pathway is involved in the control of F. solani adhesion to HCECs and that the activation of focal adhesion kinase enhances the adhesion of human corneal epithelial cells to F. solani via the tyrosine-specific protein kinase signaling pathway.
PMCID: PMC3056129  PMID: 21403855
21.  Pleural aspergillosis complicated by recurrent pneumothorax: a case report 
Pneumothorax as the first symptom of pleural aspergillosis is rare.
Case presentation
A 31-year-old asthmatic Chinese man presented with recurrent spontaneous pneumothorax and underwent lobectomy due to persistent air leakage. Aspergillus was detected histopathologically in the visceral pleural cavity. He was treated with itraconazole at 200 mg a day, and nine months later he had no recurrent pneumothorax or aspergillus infection.
Recurrent pneumothorax may be a rare manifestation of aspergillus infection. Aspergillus species infection should be considered in the differential diagnosis of recurrent pneumothorax patients, particularly those with chronic lung disease.
PMCID: PMC2898700  PMID: 20565739
22.  Hyper-IgE Syndrome with STAT3 Mutation: A Case Report in Mainland China 
Hyper-immunoglobulin E syndromes (HIES) including compound primary immunodeficiency and nonimmunological abnormalities are characterized by extremely high serum IgE levels, eosinophilia, eczema, susceptibility to infections, distinctive facial appearance, retention of deciduous teeth, cyst-forming pneumonias, and skeletal abnormalities. Itis reported that some cases of familial HIES are relative to autosomal dominant or recessive inheritance, but most cases are sporadic, and result from mutations in the human signal transducer and activator of transcription 3 (STAT3) gene. In this paper, we firstly report a young man diagnosed of Hyper-IgE syndrome with STAT3 mutation in Mainland China, and investigate the autosomal dominant trait of his family members.
PMCID: PMC2871547  PMID: 20490271
23.  Multi-gene targeted antiangiogenic therapies for experimental corneal neovascularization 
Molecular Vision  2010;16:310-319.
To determine the effectiveness of multigene-based anti-angiogenic gene therapies for experimental murine corneal neovascularization (corneal NV).
Recombinant retroviral vectors encoding murine endostatin (mEndo), murine-soluble vascular endothelial growth factor receptor-2 (msFlk-1), or murine-soluble Tie2 (msTie2) were constructed and packaged in PT67 cells. Viral titers were determined by infection of NIH3T3 cells. Expressions of mEndo, msFlk-1, and msTie2 were confirmed by reverse transcription PCR. The 3-(4,5-Dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to estimate the effect of mEndo, msFlk-1, or msTie2 on the proliferation of human umbilical vein endothelial cells, and the scarification test was used to measure the migration of the cells. Seventy C57Bl/6 mice were subjected to the induction of chemical-burn corneal NV and tested for efficacy of gene therapy. Gene therapy was performed by subconjunctival injection of viral preparations and its effect was evaluated by scoring corneal NV.
The recombinant virus-producing cell lines expressing mEndo, msFlk-1, and msTie2 were constructed successfully. Overexpression of these putative anti-angiogenic proteins inhibited the proliferation and migration of human umbilical vein endothelial cells in vitro. In the murine corneal NV model, subconjunctival injection of the retroviral particles of mEndo and msFlk-1 showed the most significant inhibition of corneal NV.
Gene therapy with the recombinant retroviral vector-hosted mEndo and msFlk-1 gene effectively inhibited corneal NV induced by alkaline burn. The combination of multiple anti-angiogenic genes might be necessary for effective therapy of corneal NV, although each of these pathways makes a potential target for the treatment of this disease.
PMCID: PMC2830023  PMID: 20208988
24.  Expression of transcription factors and crystallin proteins during rat lens regeneration 
Molecular Vision  2010;16:341-352.
To establish a model of lens regeneration in rats and to detect the expression of transcription factor and crystallin genes.
An extracapsular lens extraction (ECLE) was performed in Sprague-Dawley rats. Examinations with slit-lamp and histological analysis were performed at various time points after ECLE. Real-time PCR and/or immunofluorescence were performed to detect the expression of the lens transcription factors paired box 6 (Pax6), prospero homeobox 1 (Prox1), and forkhead box E3 (Foxe3) and α-, β-, and γ-crystallin (Cryaa, Cryab, Crybb1, Crybb2, Cryba2, and Crygd, respectively).
Lens epithelial cells (LECs) were left behind under the anterior capsule immediately after ECLE. Lens fiber differentiation had occurred in the peripheral capsular bag in all rats 3 days after ECLE. One month after surgery, all capsular bags were filled with new semitransparent lenticular structures displaying an established equator with well differentiated bow regions. The mRNA-expression quantity of lens transcription factors and α-, β-, and γ- crystallin increased after ECLE. Pax6 was expressed in both LECs and the newly regenerated lens fiber cells, Prox1 was expressed both in LECs and differentiating lens fiber cells, and Foxe3 was confined to LECs.
Lens fiber differentiation during regeneration follows a process similar to embryological development, with proliferation of epithelial cells along the anterior and posterior capsule, elongation of the posterior epithelial cells, and differentiation of epithelial cells into lens fibers. The regenerated lens contains proteins and transcription factors similar to those found in normal lenses. Inductive interactions seen during lens development are not necessary for lens regeneration.
PMCID: PMC2834568  PMID: 20216939
25.  Inhibitory effects of polysaccharide extract from Spirulina platensis on corneal neovascularization 
Molecular Vision  2009;15:1951-1961.
To assess the effects of polysaccharide extract from Spirulina platensis (PSP) on corneal neovascularization (CNV) in vivo and in vitro.
PSP was extracted from dry powder of Spirulina platensis. Its anti-angiogenic activity was evaluated in the mouse corneal alkali burn model after topical administration of PSP four times daily for up to seven days. Corneal samples were processed for histochemical, immunohistochemical, and gene expression analyses. The effects of PSP on proliferation, migration, tube formation, and serine threonine kinase (AKT) and extracellular regulated kinase1/2 (ERK1/2) signaling levels in vascular endothelial cells were determined using 3-(4,5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) and carboxyfluorescein succinimidyl ester (CFSE) labeling assays, wound healing assay, Matrigel tube formation assay, and western blot.
Topical application of PSP significantly inhibited CNV caused by alkali burn. Corneas treated with PSP showed reduced levels of platelet endothelial cell adhesion molecule (CD31) and stromal cell-derived factor 1 (SDF1) proteins, reduced levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-9 (MMP9), SDF1, and tumor necrosis factor-alpha (TNF-α) mRNAs, and an increased level of pigment epithelium-derived factor (PEDF) mRNA. These are parameters that have all been related to CNV and/or inflammation. In human vascular endothelial cells, PSP significantly inhibited proliferation, migration, and tube formation in a dose-dependent manner. Furthermore, PSP also decreased the levels of activated AKT and ERK 1/2.
These data suggest that polysaccharide extract from Spirulina platensis is a potent inhibitor of CNV and that it may be of benefit in the therapy of corneal diseases involving neovascularization and inflammation.
PMCID: PMC2751803  PMID: 19784394

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