Publications by authors named "Jia-Shu Chen"

23 Publications

  • Page 1 of 1

Postoperative Admission of Adult Craniotomy Patients to the Neuroscience Ward Reduces Length of Stay and Cost.

Neurosurgery 2021 Jun;89(1):85-93

Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Background: The neurointensive care unit (NICU) has traditionally been the default recovery unit after elective craniotomies.

Objective: To assess whether admitting adult patients without significant comorbidities to the neuroscience ward (NW) instead of NICU for recovery resulted in similar clinical outcome while reducing length of stay (LOS) and hospitalization cost.

Methods: We retrospectively analyzed the clinical and cost data of adult patients undergoing supratentorial craniotomy at a university hospital within a 5-yr period who had a LOS less than 7 d. We compared those admitted to the NICU for 1 night of recovery versus those directly admitted to the NW.

Results: The NICU and NW groups included 340 and 209 patients, respectively, and were comparable in terms of age, ethnicity, overall health, and expected LOS. NW admissions had shorter LOS (3.046 vs 3.586 d, P < .001), and independently predicted shorter LOS in multivariate analysis. While the NICU group had longer surgeries (6.8 vs 6.4 h), there was no statistically significant difference in the cost of surgery. The NW group was associated with reduced hospitalization cost by $3193 per admission on average (P < .001). Clinically, there were no statistically significant differences in the rate of return to Operating Room, Emergency Department readmission, or hospital readmission within 30 d.

Conclusion: Admitting adult craniotomy patients without significant comorbidities, who are expected to have short LOS, to NW was associated with reduced LOS and total cost of admission, without significant differences in postoperative clinical outcome.
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http://dx.doi.org/10.1093/neuros/nyab089DOI Listing
June 2021

miRNA-mediated loss of m6A increases nascent translation in glioblastoma.

PLoS Genet 2021 03 8;17(3):e1009086. Epub 2021 Mar 8.

Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence Rhode Island, United States of America.

Within the glioblastoma cellular niche, glioma stem cells (GSCs) can give rise to differentiated glioma cells (DGCs) and, when necessary, DGCs can reciprocally give rise to GSCs to maintain the cellular equilibrium necessary for optimal tumor growth. Here, using ribosome profiling, transcriptome and m6A RNA sequencing, we show that GSCs from patients with different subtypes of glioblastoma share a set of transcripts, which exhibit a pattern of m6A loss and increased protein translation during differentiation. The target sequences of a group of miRNAs overlap the canonical RRACH m6A motifs of these transcripts, many of which confer a survival advantage in glioblastoma. Ectopic expression of the RRACH-binding miR-145 induces loss of m6A, formation of FTO/AGO1/ILF3/miR-145 complexes on a clinically relevant tumor suppressor gene (CLIP3) and significant increase in its nascent translation. Inhibition of miR-145 maintains RRACH m6A levels of CLIP3 and inhibits its nascent translation. This study highlights a critical role of miRNAs in assembling complexes for m6A demethylation and induction of protein translation during GSC state transition.
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http://dx.doi.org/10.1371/journal.pgen.1009086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971852PMC
March 2021

Design, synthesis and in vitro anticancer research of novel tetrandrine and fangchinoline derivatives.

Bioorg Chem 2021 Apr 4;109:104694. Epub 2021 Feb 4.

Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan 250100, PR China. Electronic address:

Cancer treatment is one of the major public health issues in the world. Tetrandrine (Tet) and fangchinoline (d-Tet) are two bis-benzyl isoquinoline alkaloids extracted from Stephania tetrandra S. Moore, and their antitumor activities have been confirmed. However, the effective dose of Tet and d-Tet were much higher than that of the positive control and failed to meet clinical standards. Therefore, in this study, as a continuation of our previous work to study and develop high-efficiency and low-toxic anti-tumor lead compounds, twenty new Tet and d-Tet derivatives were designed, synthesized and evaluated as antitumor agents against six cancer cell lines (H460, H520, HeLa, HepG-2, MCF-7, SW480 cell lines) and BEAS-2B normal cells by CCK-8 analysis. Ten derivatives showed better cytotoxic effects than the parent fangchinoline, of which 4g showed the strongest cell growth inhibitory activity with an IC value of 0.59 μM against A549 cells. Subsequently, the antitumor mechanism of 4g was studied by flow cytometry, Hoechst 33258, JC-1 staining, cell scratch, transwell migration, and Western blotting assays. These results showed that compound 4g could inhibit A549 cell proliferation by arresting the G2/M cell cycle and inhibiting cell migration and invasion by reducing MMP-2 and MMP-9 expression. Meanwhile, 4g could induce apoptosis of A549 cells through the intrinsic pathway regulated by mitochondria. In addition, compound 4g inhibited the phosphorylation of PI3K, Akt and mTOR, suggesting a correlation between blocking the PI3K/Akt/mTOR pathway and the above antitumor activities. These results suggest that compound 4g may be a future drug for the development of new potential drug candidates against lung cancer.
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http://dx.doi.org/10.1016/j.bioorg.2021.104694DOI Listing
April 2021

Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma.

Sci Rep 2020 10 16;10(1):17580. Epub 2020 Oct 16.

Department of Neurological Surgery, University of California San Francisco, San Francisco, USA.

Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan-Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (R = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.
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http://dx.doi.org/10.1038/s41598-020-73793-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567862PMC
October 2020

WHO Grade I Meningioma Recurrence: Identifying High Risk Patients Using Histopathological Features and the MIB-1 Index.

Front Oncol 2020 28;10:1522. Epub 2020 Aug 28.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States.

In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence. A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007 to 2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (>24 months post-treatment) recurrence. A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy (2/239) or gamma knife treatment (2/239). The incidence of recurrence was 10.9% (26/239 patients), with an average time to recurrence of 33.2 months (6-105 months). Posterior fossa tumor location ( = 0.004), MIB-1 staining ( = 0.008), nuclear atypia ( = 0.003), and STR ( < 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 >4.5% had a similar incidence of recurrence as those with STR (18.8 vs. 18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR ( = 0.002) and nuclear atypia ( = 0.019). RPA confirmed STR as associated with early recurrence. STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index >4.5% is prognostic for recurrence in patients with GTR. Verification of our findings in larger, multi-institutional studies could enable risk stratification and recommendations for adjuvant radiotherapy following resection of WHO grade I meningiomas.
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http://dx.doi.org/10.3389/fonc.2020.01522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483477PMC
August 2020

Epilepsy surgery for Rasmussen encephalitis: the UCLA experience.

J Neurosurg Pediatr 2020 Jul 17:1-9. Epub 2020 Jul 17.

Departments of1Neurosurgery.

Objective: Rasmussen encephalitis (RE) is a rare inflammatory neurological disorder typically involving one hemisphere and resulting in drug-resistant epilepsy and progressive neurological decline. Here, the authors present seizure outcomes in children who underwent epilepsy surgery for RE at a single institution.

Methods: The records of consecutive patients who had undergone epilepsy surgery for RE at the UCLA Mattel Children's Hospital between 1982 and 2018 were retrospectively reviewed. Basic demographic information, seizure history, procedural notes, and postoperative seizure and functional outcome data were analyzed.

Results: The cohort included 44 patients, 41 of whom had sufficient data for analysis. Seizure freedom was achieved in 68%, 48%, and 22% of the patients at 1, 5, and 10 years, respectively. The median time to the first seizure for those who experienced seizure recurrence after surgery was 39 weeks (IQR 11-355 weeks). Anatomical hemispherectomy, as compared to functional hemispherectomy, was independently associated with a longer time to postoperative seizure recurrence (HR 0.078, p = 0.03). There was no statistically significant difference in postoperative seizure recurrence between patients with complete hemispherectomy and those who had less-than-hemispheric surgery. Following surgery, 68% of the patients could ambulate and 84% could speak regardless of operative intervention.

Conclusions: A large proportion of RE patients will have seizure relapse after surgery, though patients with anatomical hemispherectomies may have a longer time to postoperative seizure recurrence. Overall, the long-term data in this study suggest that hemispheric surgery can be seen as palliative treatment for seizures rather than a cure for RE.
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http://dx.doi.org/10.3171/2020.4.PEDS2098DOI Listing
July 2020

Seizure outcomes in children with Rasmussen's encephalitis undergoing resective or hemispheric epilepsy surgery: an individual participant data meta-analysis.

J Neurosurg Pediatr 2019 Dec 6:1-10. Epub 2019 Dec 6.

2Department of Neurosurgery, University of California, Los Angeles, California.

Objective: The objective of this study was to perform an individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Rasmussen's encephalitis (RE) undergoing resective or hemispheric epilepsy surgery.

Methods: Electronic databases (PubMed, Web of Science, CINAHL) were searched with no language or date restrictions to identify cohort studies of consecutive participants undergoing resective surgery that reported seizure outcomes. The authors recorded all preoperative factors that could plausibly be associated with seizure outcomes and used Cox regression analysis to identify which of these variables were associated with seizure freedom (i.e., Engel class I).

Results: Of 720 citations, 19 articles reporting on 187 participants were eligible. Seizure freedom (Engel class I) was observed in 113 participants (60.4%). On univariate analyses, younger age at disease onset (hazard ratio [HR] 0.906, p = 0.001), younger age at surgery (HR 0.928, p < 0.001), shorter time to surgery (HR 0.921, p = 0.001), and hemispherectomy (HR 0.283, p < 0.001) were all associated with longer time to postoperative seizure recurrence. Additionally, multivariable analysis including the aforementioned variables showed that younger age at surgery (HR 0.946, p = 0.043) and hemispherectomy (HR 0.297, p < 0.001) were independently and significantly associated with a greater time to seizure recurrence and longer duration of seizure freedom.

Conclusions: The majority of pediatric patients undergoing resective or hemispheric surgery for RE achieve good seizure outcome. Although small retrospective cohort studies are inherently prone to bias, the best available evidence utilizing individual participant data suggests hemispheric surgery and younger age at surgery are associated with good seizure outcomes following epilepsy surgery. Large, multicenter observational studies with long-term follow-up are required to evaluate the risk factors identified in this review.
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http://dx.doi.org/10.3171/2019.9.PEDS19380DOI Listing
December 2019

The neurosurgery applicant's "arms race": analysis of medical student publication in the Neurosurgery Residency Match.

J Neurosurg 2019 Nov 1:1-9. Epub 2019 Nov 1.

Objective: Neurosurgery is consistently one of the most competitive specialties for resident applicants. The emphasis on research in neurosurgery has led to an increasing number of publications by applicants seeking a successful residency match. The authors sought to produce a comprehensive analysis of research produced by neurosurgical applicants and to establish baseline data of neurosurgery applicant research productivity given the increased emphasis on research output for successful residency match.

Methods: A retrospective review of publication volume for all neurosurgery interns in 2009, 2011, 2014, 2016, and 2018 was performed using PubMed and Google Scholar. Missing data rates were 11% (2009), 9% (2011), and < 5% (all others). The National Resident Matching Program report "Charting Outcomes in the Match" (ChOM) was interrogated for total research products (i.e., abstracts, presentations, and publications). The publication rates of interns at top 40 programs, students from top 20 medical schools, MD/PhD applicants, and applicants based on location of residency program and medical school were compared statistically against all others.

Results: Total publications per neurosurgery intern (mean ± SD) based on PubMed and Google Scholar were 5.5 ± 0.6 in 2018 (1.7 ± 0.3, 2009; 2.1 ± 0.3, 2011; 2.6 ± 0.4, 2014; 3.8 ± 0.4, 2016), compared to 18.3 research products based on ChOM. In 2018, the mean numbers of publications were as follows: neurosurgery-specific publications per intern, 4.3 ± 0.6; first/last author publications, 2.1 ± 0.3; neurosurgical first/last author publications, 1.6 ± 0.2; basic science publications, 1.5 ± 0.2; and clinical research publications, 4.0 ± 0.5. Mean publication numbers among interns at top 40 programs were significantly higher than those of all other programs in every category (p < 0.001). Except for mean number of basic science publications (p = 0.1), the mean number of publications was higher for interns who attended a top 20 medical school than for those who did not (p < 0.05). Applicants with PhD degrees produced statistically more research in all categories (p < 0.05) except neurosurgery-specific (p = 0.07) and clinical research (p = 0.3). While there was no statistical difference in publication volume based on the geographical location of the residency program, students from medical schools in the Western US produced more research than all other regions (p < 0.01). Finally, research productivity did not correlate with likelihood of medical students staying at their home institution for residency.

Conclusions: The authors found that the temporal trend toward increased total research products over time in neurosurgery applicants was driven mostly by increased nonindexed research (abstracts, presentations, chapters) rather than by increased peer-reviewed publications. While we also identified applicant-specific factors (MD/PhDs and applicants from the Western US) and an outcome (matching at research-focused institutions) associated with increased applicant publications, further work will be needed to determine the emphasis that programs and applicants will need to place on these publications.
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http://dx.doi.org/10.3171/2019.8.JNS191256DOI Listing
November 2019

Social Media Use for Professional Purposes in the Neurosurgical Community: A Multi-Institutional Study.

World Neurosurg 2019 Sep 25;129:e367-e374. Epub 2019 May 25.

Department of Neurosurgery, Los Angeles (UCLA), Los Angeles, California, USA; Department of Radiation Oncology, Los Angeles (UCLA), Los Angeles, California, USA; Department of Head and Neck Surgery, Los Angeles (UCLA), Los Angeles, California, USA; Jonsson Comprehensive Cancer Center, Los Angeles (UCLA), Los Angeles, California, USA; Los Angeles Biomedical Research Institute, Los Angeles (UCLA), Los Angeles, California, USA; Harbor-UCLA Medical Center, Los Angeles (UCLA), Los Angeles, California, USA; David Geffen School of Medicine of the University of California, Los Angeles (UCLA), Los Angeles, California, USA. Electronic address:

Background: Since the debut of Facebook in 2004, social media (SoMe) has garnered increased popularity and usage worldwide. Given its appeal and visibility, many industries have used SoMe to promote products for professional purposes. Specialized sites have subsequently been created to connect users in similar disciplines. Although SoMe sites have amassed over 1-billion followers, SoMe usage in the neurosurgical community has not yet been well described.

Methods: We present an online survey administered to neurosurgery faculty, fellows, and residents in 102 U.S. accredited programs to gauge usage and perception of SoMe for professional purposes.

Results: Of all surveys distributed, 241 neurosurgeons responded with an attending, resident, to fellow breakdown of 137, 96, and 8, respectively. A total of 55.97% of respondents were under the age of 34, 2% were over the age of 75, and 81% of respondents identified as men. An overwhelming majority cited conferences (83%) and in-person meetings as their preferred method of networking. However, 70% state they use SoMe for professional purposes with Doximity and LinkdIn listed as the most popular (49% and 48%, respectively) platforms. Lack of time and perceived value, in addition to privacy concerns, were noted to be the main factors for those refraining from SoMe use.

Conclusions: As SoMe becomes increasingly popular and its use expands, the majority of neurosurgeon respondents are also using SoMe for professional purposes. Although lack of time, lack of perceived value, and privacy concerns were hindrances to usage, other factors like age do not seem to correlate with SoMe adoption for professional aims.
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http://dx.doi.org/10.1016/j.wneu.2019.05.154DOI Listing
September 2019

Prediction of post-operative delayed hyponatremia after endoscopic transsphenoidal surgery.

Clin Neurol Neurosurg 2019 07 13;182:87-91. Epub 2019 May 13.

Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, USA. Electronic address:

Objectives: Delayed symptomatic hyponatremia is a known phenomenon occurring > 3 days after transsphenoidal surgery. This is a significant cause of post-operative emergency room visits and re-admissions. We describe and characterize post-operative hyponatremia in patients undergoing endoscopic transsphenoidal surgery, identify predictive factors, and create a clinical tool for predicting high risk patients.

Patients & Methods: We retrospectively reviewed a series of over 300 consecutive patients undergoing endoscopic transsphenoidal surgery and identified patients with delayed hyponatremia as well as patient, tumor, and surgical characteristics. In addition, we recorded inpatient post-operative sodium and specific gravity values as well as treatment upond discharge. Univariate and multivariate analyses were carried out to identify predictors of delayed hyponatremia and stratify patients into risk groups.

Results: We found that 15% of patients developed delayed hyponatremia and that this occurred most commonly on post-operative day 7. This accounted for more than half of re-admissions after this type of surgery. Female patients and patients needing fluid restriction or fludrocortisone upon discharge were more likely to develop delayed hyponatremia. Patients with post-operative diabetes insipidus were less likely to develop delayed hyponatremia. Using ROC analysis we developed a score which reliably could stratify patients at risk for delayed hyponatremia.

Conclusions: We confirm the risk of delayed hyponatremia after transphenoidal surgery and identify factors that are revealed before discharge to identify patients at higher risk of delayed hyponatremia. These data may help identify patients who require treatment upon discharge and short interval follow up to avoid significant costs of re-admission.
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http://dx.doi.org/10.1016/j.clineuro.2019.05.007DOI Listing
July 2019

Age-related differences in social media use in the neurosurgical community: A multi-institutional study.

Clin Neurol Neurosurg 2019 05 1;180:97-100. Epub 2019 Apr 1.

Departments of Neurosurgery, Los Angeles (UCLA), Los Angeles, CA, United States; Departments of Radiation Oncology, Los Angeles (UCLA), Los Angeles, CA, United States; Departments of Head and Neck Surgery, Los Angeles (UCLA), Los Angeles, CA, United States; Departments of Jonsson Comprehensive Cancer Center, Los Angeles (UCLA), Los Angeles, CA, United States; Departments of Los Angeles Biomedical Research Institute, Los Angeles (UCLA), Los Angeles, CA, United States; Departments of Harbor-UCLA Medical Center, Los Angeles (UCLA), Los Angeles, CA, United States; Departments of David Geffen School of Medicine of the University of California, Los Angeles (UCLA), Los Angeles, CA, United States. Electronic address:

Objectives: Social media is evolving and growing at an exponential rate today. From a healthcare perspective, these platforms can be used to enhance professional networking, education, organizational promotion, patient care, patient education, and public health programs without the limitations of geographic and time-related access barriers. Given the possible importance of social media in medicine, and the conflicting reports in literature about its use in healthcare, it is important to identify its utility within the neurosurgical community. We set out to measure the use of social media platforms among neurosurgery faculty, fellows, and residents.

Patients And Methods: An online survey using the SurveyMonkey platform was sent to the program directors of 102 accredited neurosurgery programs across the United States. Program directors then distributed these surveys to the residents, fellows, and attendings at their respective institutions once each month between October 2017 and December 2017. Neurosurgeons participated anonymously, voluntarily, and received no compensation for their participation. Statistical analysis was performed using the IBM SPSS Statistics for Windows, Version 25 (IBM SPSS Statistics for Windows, IBM Corporation, Armonk, NY).

Results: 137 attendings, 96 residents, and 8 fellows responded to the survey (81% male). Most (70%) stated that they used social media for professional purposes. Sixty percent of all respondents believed that social media can be beneficial in terms of professional development. Younger neurosurgeons in training were more likely to read journal articles found via social media and were more likely to believe social media could be beneficial than older neurosurgeons at later stages in their career.

Conclusions: Results point toward differences in social media use based on age or level of training. Further studies should include a larger sample cohort over a longer time period to determine whether these trends will change over time.
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http://dx.doi.org/10.1016/j.clineuro.2019.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488041PMC
May 2019

Predicting mortality in traumatic intracranial hemorrhage.

J Neurosurg 2019 02;132(2):552-559

1Department of Neurosurgery, Warren Alpert Medical School of Brown University.

Objective: Traumatic intracranial hemorrhage (tICH) is a significant source of morbidity and mortality in trauma patients. While prognostic models for tICH outcomes may assist in alerting clinicians to high-risk patients, previously developed models face limitations, including low accuracy, poor generalizability, and the use of more prognostic variables than is practical. This study aimed to construct a simpler and more accurate method of risk stratification for all tICH patients.

Methods: The authors retrospectively identified a consecutive series of 4110 patients admitted to their institution's level 1 trauma center between 2003 and 2013. For each admission, they collected the patient's sex, age, systolic blood pressure, blood alcohol concentration, antiplatelet/anticoagulant use, Glasgow Coma Scale (GCS) score, Injury Severity Score, presence of epidural hemorrhage, presence of subdural hemorrhage, presence of subarachnoid hemorrhage, and presence of intraparenchymal hemorrhage. The final study population comprised 3564 patients following exclusion of records with missing data. The dependent variable under study was patient death. A k-fold cross-validation was carried out with the best models selected via the Akaike Information Criterion. These models risk stratified the study partitions into grade I (< 1% predicted mortality), grade II (1%-10% predicted mortality), grade III (10%-40% predicted mortality), or grade IV (> 40% predicted mortality) tICH. Predicted mortalities were compared with actual mortalities within grades to assess calibration. Concordance was also evaluated. A final model was constructed using the entire data set. Subgroup analysis was conducted for each hemorrhage type.

Results: Cross-validation demonstrated good calibration (p < 0.001 for all grades) with a mean concordance of 0.881 (95% CI 0.865-0.898). In the authors' final model, older age, lower blood alcohol concentration, antiplatelet/anticoagulant use, lower GCS score, and higher Injury Severity Score were all associated with greater mortality. Subgroup analysis showed successful stratification for subarachnoid, intraparenchymal, grade II-IV subdural, and grade I epidural hemorrhages.

Conclusions: The authors developed a risk stratification model for tICH of any GCS score with concordance comparable to prior models and excellent calibration. These findings are applicable to multiple hemorrhage subtypes and can assist in identifying low-risk patients for more efficient resource allocation, facilitate family conversations regarding goals of care, and stratify patients for research purposes. Future work will include testing of more variables, validation of this model across institutions, as well as creation of a simplified model whose outputs can be calculated mentally.
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http://dx.doi.org/10.3171/2018.11.JNS182199DOI Listing
February 2019

Factors associated with the progression of conservatively managed acute traumatic subdural hemorrhage.

J Crit Care 2018 12 14;48:243-250. Epub 2018 Sep 14.

Warren Alpert Medical School of Brown University, Department of Neurosurgery, Providence, RI, 02903, USA; Norman Prince Neurosciences Institute, Rhode Island Hospital, Providence, RI, 02903, USA.

Purpose: Traumatic subdural hemorrhage (SDH) is associated with high mortality, yet many patients are not managed surgically. We sought to understand what factors might be associated with SDH enlargement to contribute to the triage of these conservatively managed patients.

Materials And Methods: A consecutive series of 117 patients admitted to our institution's level 1 trauma center for SDH between January 1, 2010 and December 31, 2010 were evaluated. Volumetric measurement of SDHs was performed on initial and follow-up head computed tomography (CT) scans with recording of initial midline shift and classification by location. Multimodel analysis quantified associations with change in SDH volume.

Results: Systolic blood pressure, presence of subarachnoid hemorrhage, and initial SDH volume demonstrated positive associations with change in SDH volume, while initial midline shift and transfusion of platelets demonstrated negative associations. Initial convexity SDH volume demonstrated positive association with change in convexity SDH volume, while initial midline shift and transfusion of platelets demonstrated negative associations. Anticoagulant/antiplatelet use demonstrated positive association with change in tentorial SDH volume, while time between CT scans demonstrated negative association.

Conclusions: Platelet transfusion, anticoagulation, and hypertension have significant associations with expansion in non-surgical cases of SDH. Monitoring these factors may assist triaging these patients.
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http://dx.doi.org/10.1016/j.jcrc.2018.09.014DOI Listing
December 2018

A urinary metabolomics study of rats after the exposure to acrylamide by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry.

Mol Biosyst 2015 Apr;11(4):1146-55

Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, P. R. China.

Acrylamide (ACR) is known to induce neurotoxicity in humans and occupational exposure to ACR has an effect on human health. Since some animal experiments indicate the metabolic change caused by the ACR based on the metabolomics, increasing concern is the change of metabolite profiles by the low-dose ACR. In the present study, a low-dose of ACR (18 mg kg(-1)) was administered to male Wistar rats for 40 days. Ultra performance liquid chromatography/time of flight mass spectrometry (UPLC-Q-TOF MS) was used to examine urine samples from ACR-dosed and control animals. Multiple statistical analyses with principal component analysis (PCA) were used to investigate metabolite profile changes in urine samples, and to screen for potential neurotoxicity biomarkers. PCA showed differences between the ACR-dosed and control groups 20 days after the start of dosing; a bigger separation between the two groups was seen after dosing for 40 days. Levels of 4-guanidinobutanoic acid and 2-oxoarginine were significantly higher in urine from the ACR-dosed group than in urine from the control group after 10 days (p < 0.05). Receiver operator characteristic (ROC) curve analysis suggested that 4-guanidinobutanoic acid and 2-oxoarginine were the major metabolites. Our results suggest that high levels of 4-guanidinobutanoic acid and 2-oxoarginine may be related to ACR neurotoxicity. These metabolites could, therefore, act as sensitive biomarkers for ACR exposure and be useful for investigating toxic mechanisms. They may also provide a scientific foundation for assessing the effects of chronic low-dose ACR exposure on human health.
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http://dx.doi.org/10.1039/c4mb00682hDOI Listing
April 2015

A novel recombinant fibrinogenase of Agkistrodon acutus venom protects against hyperacute rejection via degradation of complements.

Biochem Pharmacol 2013 Mar 23;85(6):772-9. Epub 2012 Nov 23.

Department of Pharmacology, Medical College, Ji-Nan University, 601 Huangpu Road, Guangzhou, Guangdong 510632, PR China.

Hyperacute rejection (HAR) is a main barrier in xenotransplantation, which is mediated by the combination of natural antibody to the xenograft and complement activation. Current therapies have focus on the inhibition of complement by development of complement inhibitor and transgenic animal organ. Here, we investigated the effects of rFII, a recombinant fibrinogenase from Agkistrodon acutus venom, on complement and HAR. The degradation effect of rFII on complement was tested by SDS-PAGE, CH50 examination, ELISA Kit and cofocal immunofluorescence microscopy in vitro and in vivo. An ex-vivo rat-to-human perfusion model and a vivo guinea-pig-to-rat heat HAR model were used to determine the protection of rFII against HAR. Our investigation indicated that rFII could significantly degrade human C5, C6, and C9, decrease the activity of complement, and inhibit the MAC deposition on HUVECs membrane in vitro. In addition, serum levels of C1q, C3 and C4 in rat were gradually reduced after infusion of rFII. Importantly, in an ex vivo rat-to-human perfusion model, the survival of rat hearts perfused with human serum treated with rFII (83.36 ± 16.63 min) were significantly longer than that of hearts perfused with fresh human serum(15.94 ± 4.75 min). At the time of 15 minutes after perfusion, functions of hearts added with 50 ug/ml rFII sustained well with heart rates at 283 ± 65.32 beats/minute and LVDP at 13.70 ± 5.45 Kpa, while that of hearts perfused with fresh human serum were severely damaged by HAR with heart rates at 107.77 ± 40.31 beats/minute and LVDP at 1.01 ± 0.83 Kpa. We also found that rFII significantly decreased the levels of C1q, C3 and C4 in human fresh serum perfusate. In a vivo guinea-pig-to-rat heat HAR model, the survival of rat hearts treated with rFII were significantly longer than that of hearts perfused with normal saline; and relieved heart damage by complete activation. Our finding demonstrates the anti-complement property of rFII and its protection against HAR, indicating that rFII might be as a potential therapeutic agent for xenotransplantation.
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http://dx.doi.org/10.1016/j.bcp.2012.11.012DOI Listing
March 2013

A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C.

Biochem Pharmacol 2012 Oct 20;84(7):905-13. Epub 2012 Jun 20.

Department of Pharmacology, Zhongshan Medical College, SUN Yat-Sen University, Guangzhou 510080, China.

The incidence of disseminated intravascular coagulation (DIC), which leads to multiple organ dysfunction and high mortality, has remained constant in recent years. At present, treatments of DIC have focused on preventing cytokine induction, inhibiting coagulation processes and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC. To better understand the mechanism of treatment on DIC, we here report a novel fibrinogenase from Agkistrodon acutus (FIIa) that effectively protected against LPS-induced DIC in a rabbit model, and detected the tissue factors expression in HUVE cells after using FIIa. In vivo, administration of FIIa reduced hepatic and renal damage, increased the concentration of fibrinogen, the activities of protein C, the platelet count, APTT, PT, FDP, the level of AT-III and t-PA, decreased the level of PAI-1, and increased survival rate in LPS-induced DIC rabbits. In vitro experiments, we further confirmed that FIIa up-regulated the expression of t-PA and u-PA, down-regulated the expression of PAI-1, and directly activated protein C. Our findings suggest that FIIa could effectively protect against DIC via direct degradation of microthrombi and activation of protein C as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.
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http://dx.doi.org/10.1016/j.bcp.2012.06.011DOI Listing
October 2012

The effect of the fibrinolytic enzyme FIIa from Agkistrodon acutus venom on acute pulmonary thromboembolism.

Acta Pharmacol Sin 2011 Feb;32(2):239-44

Department of Pharmacology, Medical College, Ji-nan University, Guangzhou, China.

Aim: To evaluate the effects of the fibrinolytic enzyme FII(a) from Agkistrodon acutus venom on acute pulmonary thromboembolism (APT) in animal models.

Methods: Both rabbit and dog APT models were used. For the rabbit APT model, the thrombi weight before and after administration was measured. Central venous pressure (CVP) and mean arterial pressure (MAP) were measured before and 15, 30, 60, and 120 min after the injection of the blood clot. Partial thromboplastin time (APTT), prothrombin time (PT), platelet count, and fibrinogen concentration were measured using auto analyzers. Plasminogen activity was measured based on chromogenic substrates. In the dog APT model, pulmonary blood flow was recorded using pulmonary angiography.

Results: Intravenous administration of FIIa (0.1-5.0 mg/kg) improved the APT-induced hemodynamic derangements and reduced thrombi weight. The angiography evidence also showed that the pulmonary emboli had almost disappeared after FII(a) infusion. FII(a) (0.1, 0.5, or 1.0 mg/kg) did not impair the coagulation pathways, although very high doses of FII(a) (5.0 mg/kg) could stimulate the production of plasminogen and result in impairment of the pathways.

Conclusion: FII(a) could effectively protect against APT via degradation of thrombi with less activation of plasminogen, and may provide a novel fibrinolytic enzyme for targeting the main pathological processes of the disease.
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http://dx.doi.org/10.1038/aps.2010.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009945PMC
February 2011

The effect of fibrinolytic enzyme FIIa from Agkistrodon acutus venom on disseminated intravascular coagulation in rabbits.

Transl Res 2007 Nov 16;150(5):295-302. Epub 2007 Jul 16.

Department of Pharmacology, Zhongshan Medical College, SUN Yat-Sen University, Guangzhou, China.

A novel fibrinolytic enzyme, FII(a), was isolated from Agkistrodon acutus venom, which can degrade fibrin/fibrinogen and dissolve thrombus without activating plasminogen or influencing the activities of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1). In this study, we evaluated the effect of FII(a) on lipopolysaccharide (LPS)-induced experimental disseminated intravascular coagulation (DIC) in rabbits, through the continuous infusion of 100-microg/kg/h LPS for a period of 6 h. Seven groups were established: LPS control, FII(a) (0.1, 0.3, and 0.6 mg/kg/h, respectively), heparin control (100 IU/kg/h), heparin + FII(a) (heparin 100 IU/kg/h associated with FII(a) 0.3 mg/kg/h), and a saline control group. A continuous injection of LPS induced a gradual impairment in hemostatic parameters, kidney fibrin deposition, and a high mortality rate. The intravenous administration of FII(a) improved the concentration of fibrinogen, the activities of protein C, plasminogen, t-PA, antithrombin III (ATIII), and PAI-1. Kidney fibrin deposition and the mortality also decreased. In the in vitro experiments, FII(a) can degrade fibrin/fibrinogen and high-dose FII(a) enhanced the activity of protein C. These findings suggest that the effects of FII(a) on LPS-induced DIC were from fibrinogen degradation and enhanced protein C activity. The simultaneous administration of FII(a) and heparin further improved all the hemostatic parameters, including decreased kidney fibrin deposition, and none of the rabbits died within 24 h, which indicates that the effects were mediated by degradation of fibrin/fibrinogen together with thrombin inhibition. We conclude that FII(a) may be useful in the treatment of DIC.
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http://dx.doi.org/10.1016/j.trsl.2007.06.004DOI Listing
November 2007

Purification and partial characterizations of coagulant protein FIa from Daboia russelli siamensis (Myanmar) venom.

Acta Pharmacol Sin 2007 Oct;28(10):1580-4

Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou 510080, China.

Aim: To purify and characterize the coagulant protein FIa from Daboia russelli siamensis (Myanmar) venom.

Methods: FIa was purified from Daboia russelli siamensis (Myanmar) venom by ion-exchange chromatography on CM-Sephadex C-50, and gel filtration on Sephadex G-75 and a Superdex 75 column. The hemostatic activity of FIa was determined by the method of Williams and Esnouf. The specific chromogenic substrates were used respectively to determine the activation of factor X and prothrombin. The fibrinogen-clotting activity of FIa was determined by the method of Gao et al. Normal saline was used as a negative control while factor Xa and thrombin were used as positive controls, respectively.

Results: FIa, a coagulant protein, was achieved by ion-exchange chromatography and gel filtration with a molecular weight of 34,479 and an isoelectric point of 7.2. FIa was shown to have strong hemostatic activity. The hemostatic activity of 0.5 mg FIa was equal to that of 1.5625 u thrombin. FIa primarily activated factor X, however, had no influence on prothrombin, nor did it cleave or clot fibrinogen.

Conclusion: FIa is a factor X-activating enzyme, which could activate factor X to factor Xa, but has no effect on prothrombin and fibrinogen.
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http://dx.doi.org/10.1111/j.1745-7254.2007.00616.xDOI Listing
October 2007

Expression, purification and molecular modeling of recombinant fibrinogenase [IV], a metalloproteinase from Deinakistrodon acutus venom.

Toxicon 2006 Feb 28;47(2):241-8. Epub 2005 Dec 28.

Department of Pharmacology, Sun Yat-sen University, Sun Yat-sen Medical School, 74 Zhongshan II Road, Guangzhou 510080, China.

A novel metalloproteinase, recombinant fibrinogenase IV (rFIV(a)), was expressed and purified from Deinakistrodon acutus venom. It was a single chain protein with an apparent molecular weight 27 kDa and an isoeletric point of pH 7.1. RFIV(a) cleaved preferentially the Aalpha-chain and also cleaved Bbeta, gamma-chains of fibrinogen when the incubation time was prolonged. The proteolytic activity was inhibited by EDTA, l-cysteine, and DTT, indicating rFIV(a) was a metalloproteinase requiring disulfide bonds for its activity. It kept above 85% of the initial activity from pH 4.5-11, showed an equal maximum activity at the temperature range from 30 to 50 degrees C, and was inactivated by Zn2+, Cu2+ and Cd2+. Homology modeling of rFIV(a) showed that two highly conserved disulfide bonds (Cys159-Cys164 and Cys117-Cys197) was maintained from its structure, and it exhibited the characteristic conserved motif H142E143XXH146XXGXXH152, whose three histidine residues were involved in binding of the catalytically essential zinc ion. This work demonstrates the expression, purification and characterization of recombinant fibrinogenase IV, which belongs to class P-I metalloproteinase from D. acutus venom.
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http://dx.doi.org/10.1016/j.toxicon.2005.11.005DOI Listing
February 2006

Enzymological characterization of FII(a), a fibrinolytic enzyme from Agkistrodon acutus venom.

Acta Pharmacol Sin 2005 Dec;26(12):1474-8

Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou 510080, China.

Aim: To study the enzymological characterization of a fibrinolytic enzyme (FII(a)) from Agkistrodon acutus venom.

Methods: The fibrinogenolytic effect and the influences of several protease inhibitors, chelating agents, and metal ions on fibrinogenolytic activity were visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The metal content of FII(a) was determined by atomic absorption spectroscopy.

Results: After incubation with FII(a) (0.25 g/L), Aalpha-, Bbeta- and gamma-chains of fibrinogen disappeared within 5 min, 30 min, and 8 h , respectively. The molecular weights of major degradation products were 45,000 and 41,000, which were different from those bands produced by plasmin. The fibrinogenolytic activity of FIIa was strongly inhibited by ethylenediamine tetraacetic acid (EDTA), ethyleneglycol tetraacetic acid (EGTA), dithiothreitol and cysteine, but not by phenylmethyl-sulfonyl fluoride and soybean trypsin inhibitor. Zinc (3171+/-25 mg/kg), potassium (489+/-17 mg/kg) and calcium (319+/-13 mg/kg) were found in FIIa. Zn2+, Ca2+ and Mg2+ could recover the fibrinogenolytic activity of FIIa, which was inhibited by EDTA. Only Ca2+ could recover the fibrinogenolytic activity inhibited by EGTA.

Conclusion: FIIa can degrade the Aalpha-, Bbeta- and gamma-chains of fibrinogen. FII(a) is a metalloproteinase, and Zn2+, Ca2+, and disulfide bonds are necessary for its fibrinogenolytic activity.
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http://dx.doi.org/10.1111/j.1745-7254.2005.00204.xDOI Listing
December 2005

Fibrin(ogen)olytic character of FIIa isolated from Agkistrodon acutus venom.

Acta Pharmacol Sin 2005 Jun;26(6):691-5

Department of Pharmacology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou 510080, China.

Aim: To investigate the fibrin(ogen)olytic character of FIIa isolated from Agkistrodon acutus venom in vitro and in vivo.

Methods: 125I-labeled human plasma clot lysis was measured in vitro and rabbit carotid artery thrombosis was as an in vivo model.

Results: In vitro, urokinase (UK) at 25, 35, 40, 45, 60 kU/L and FIIa at 0.08, 0.23, 0.4, 0.5, and 0.7 g/L resulted an equivalent clot lysis (20%, 40%, 50%, 60%, and 80%). UK at 25 to approximately 60 kU/L induced 27.3%+/-3.6%, 35.2%+/-2.3%, 39.3%+/-2.4%, 44.2%+/-4.6%, and 51.1%+/-1.2% fibrinogen degradation. But FIIa at 0.08 approximately -0.7 g/L induced 95.4%+/-0.3%, >95.6%, >95.6%, >95.6%, >95.6% fibrinogen degradation respectively. In vivo, UK 40 kU/kg and FIIa 1.0 mg/kg reduced the weight of residual thrombus to 9.0+/-2.5 mg and 7.8+/-3.5 mg compared with negative control group (30.0+/-5.4 mg). But the fibrinogen degradation rate after UK 40 kU/kg and FIIa 1.0 mg/kg treatment was 24.4%+/-6.2% and 4.1%+/-7.8%, respectively (P<0.05, n=6). The order of the lysis speed after UK 125 kU/L treatment was platelet poor plasma (PPP) clots>the whole blood clots>platelet rich plasma (PRP) clots. The sequence for FIIa 0.4 g/L was PRP >PPP >whole blood clots.

Conclusion: At the same percentage of clot lysis, FIIa degraded more fibrinogen than UK did in vitro but less fibrinogen than UK did in vivo. The order of the lysis speed was PPP>whole blood clots>PRP clots for UK and PRP>PPP>whole blood clots for FIIa.
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http://dx.doi.org/10.1111/j.1745-7254.2005.00099.xDOI Listing
June 2005

Hemorrhagic activity and mechanism of FIIa, a fibrinolytic enzyme from Agkistrodon acutus venom.

Acta Pharmacol Sin 2004 Apr;25(4):514-21

Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou 510080, China.

Aim: To study the local hemorrhagic activity of a fibrinolytic enzyme (FII(a)) from Agkistrodon acutus venom and its mechanism.

Methods: The local hemorrhagic activity was determined by subcutaneous injection on the back of mouse. The effects of FIIa on factor X, prothrombin, gelatin, and collagen were visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Platelet aggregation assays were performed in rat platelet-rich plasma (PRP). Human umbilical vein endothelial cells (HUVEC) were cultured and passaged in complete M199 medium. Cell viability and nuclear morphology change were determined by fluorescein diacetate (FDA) staining and Hoechst 33258 staining, respectively.

Results: The minimum hemorrhagic dose (MHD) of FIIa was 89 microg. In vitro, FII(a) (0.25 g/L) degraded factor X, prothrombin, collagen, and gelatin, and dose-dependently (0.25, 0.50, 0.75, and 1.00 g/L) inhibited the platelet aggregation induced by ADP in rat PRP. When HUVEC in culture treated with FII(a), HUVEC showed detachment in a dose-dependent manner, but no apoptosis sign was observed.

Conclusion: FIIa had local hemorrhagic activity, and the mechanism was related to the degradation of factor X, prothrombin, gelatin, and collagen, the inhibition of ADP-induced platelet aggregation, and inducement of HUVEC detachment.
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April 2004
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