Publications by authors named "Yiyu Deng"

26 Publications

  • Page 1 of 1

Urinary Trypsin Inhibitor Protects Tight Junctions of Septic Pulmonary Capillary Endothelial Cells by Regulating the Functions of Macrophages.

J Inflamm Res 2021 17;14:1973-1989. Epub 2021 May 17.

Department of Intensive Care Unit, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, People's Republic of China.

Background: Our previous study found that urinary trypsin inhibitor (ulinastatin, UTI) protected tight junctions (TJs) of lung endothelia via TNF-α inhibition, thereby alleviating pulmonary capillary permeability in septic rats. As the activated macrophage is the main source of TNF-α in sepsis, we speculate that UTI may exert the above effects by regulating the functions of macrophages.

Methods: Bone-marrow derived macrophages (BMDM) were divided into control, lipopolysaccharide (LPS), UTI+LPS and UTI groups. TNF-α, TGF-β, IL-10, CD86, CD206 and MCP-1 expression were assessed by Western blot. The phagocytosis and migration of BMDM were detected. Pulmonary microvascular endothelial cells (PMVECs) were cultured with the conditioned medium (CM) from each group of BMDM above. Sprague-Dawley rats were divided into sham, cecal ligation and puncture (CLP), and UTI+CLP groups. Western blot and immunofluorescence were used to detected zonula occludens-1 (ZO-1), occludin and claudin-5 expression in PMVECs, as well as TNF-α, TGF-β, iNOS, CD86 and CD206 expression in lungs. Pulmonary capillary permeability was assessed by extravasated Evans blue, lung injury score (LIS), wet-to-dry weight ratio and electron microscope.

Results: TNF-α and CD86 expression were increased in LPS-treated BMDM, but were reversed by UTI pretreatment. TGF-β, IL-10 and CD206 expression were the opposite. UTI markedly decreased phagocytosis and migration of LPS-treated BMDM. ZO-1, occludin and claudin-5 expression were markedly decreased in PMVECs of the CM-LPS group, but significantly increased in the CM-UTI+LPS group. TNF-α, iNOS and CD86 expression were increased in the lungs of CLP-rats but decreased with UTI pretreatment, while TGF-β and CD206 expression were the opposite. UTI markedly ameliorated the lung EB leakage, improved LIS, reduced the wet-to-dry ratio and revised the damaged TJs of PMVECs in CLP-rats.

Conclusion: UTI effectively inhibits the conversion of M1 macrophage but increases M2, reduces the phagocytosis and migration, which helps to protect endothelia TJs and reduce pulmonary capillary permeability during sepsis.
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http://dx.doi.org/10.2147/JIR.S303577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149216PMC
May 2021

A nomogram incorporating functional and tubular damage biomarkers to predict the risk of acute kidney injury for septic patients.

BMC Nephrol 2021 May 13;22(1):176. Epub 2021 May 13.

Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, 510080, Guangzhou, PR China.

Background: Combining tubular damage and functional biomarkers may improve prediction precision of acute kidney injury (AKI). Serum cystatin C (sCysC) represents functional damage of kidney, while urinary N-acetyl-β-D-glucosaminidase (uNAG) is considered as a tubular damage biomarker. So far, there is no nomogram containing this combination to predict AKI in septic cohort. We aimed to compare the performance of AKI prediction models with or without incorporating these two biomarkers and develop an effective nomogram for septic patients in intensive care unit (ICU).

Methods: This was a prospective study conducted in the mixed medical-surgical ICU of a tertiary care hospital. Adults with sepsis were enrolled. The patients were divided into development and validation cohorts in chronological order of ICU admission. A logistic regression model for AKI prediction was first constructed in the development cohort. The contribution of the biomarkers (sCysC, uNAG) to this model for AKI prediction was assessed with the area under the receiver operator characteristic curve (AUC), continuous net reclassification index (cNRI), and incremental discrimination improvement (IDI). Then nomogram was established based on the model with the best performance. This nomogram was validated in the validation cohort in terms of discrimination and calibration. The decision curve analysis (DCA) was performed to evaluate the nomogram's clinical utility.

Results: Of 358 enrolled patients, 232 were in the development cohort (69 AKI), while 126 in the validation cohort (52 AKI). The first clinical model included the APACHE II score, serum creatinine, and vasopressor used at ICU admission. Adding sCysC and uNAG to this model improved the AUC to 0.831. Furthermore, incorporating them significantly improved risk reclassification over the predictive model alone, with cNRI (0.575) and IDI (0.085). A nomogram was then established based on the new model including sCysC and uNAG. Application of this nomogram in the validation cohort yielded fair discrimination with an AUC of 0.784 and good calibration. The DCA revealed good clinical utility of this nomogram.

Conclusions: A nomogram that incorporates functional marker (sCysC) and tubular damage marker (uNAG), together with routine clinical factors may be a useful prognostic tool for individualized prediction of AKI in septic patients.
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http://dx.doi.org/10.1186/s12882-021-02388-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120900PMC
May 2021

Nomogram to predict survival outcome of patients with veno-arterial extracorporeal membrane oxygenation after refractory cardiogenic shock.

Postgrad Med 2021 May 20:1-10. Epub 2021 May 20.

Department of Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Gaozhou, Guangdong, China.

: This study aims to develop a nomogram model to predict the survival of refractory cardiogenic shock (RCS) patients that received veno-arterial extracorporeal membrane oxygenation (VA-ECMO).: A total of 235 and 209 RCS patients were supported with VA-ECMO from January 2018 to December 2019 in Guangdong Provincial People's Hospital, and from January 2020 to December 2020 in four third-grade and class-A hospitals were a development cohort (DC) and validation cohort (VC), respectively. Finally, 137 and 98 patients were included in the DC and VC. Multivariate logistic regression analysis was used to identify variables, and only these independent risk factors were used to establish the nomogram model. The receiver operating characteristic curve (ROC), calibration plot, decision curve, and clinical impact curves were used to evaluate the nomogram's discriminative ability, predictive accuracy, and clinical application value.: Pre-ECMO cardiogenic arrest (pre-ECA), lactate (Lac), inotropic score (IS), and modified nutrition risk in the critically ill score (mNUTRIC score) were incorporated into the nomogram. This showed good discrimination in the DC, with an area under ROC (AUROC) and a 95% confidence interval (CI) of 0.959 (0.911-0.986). The AUROC (95% CI) of the VC was 0.928 (0.858-0.971). The calibration plots of the DC and VC presented good calibration results. The decision curve and clinical impact curve of the nomogram provided improved benefits for RCS patients.: This study established a prediction nomogram composed of pre-ECA, Lac, IS, and mNUTRIC scores that could help clinicians to predict the survival probability at hospital discharge precisely and rapidly for RCS patients that received VA-ECMO.
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http://dx.doi.org/10.1080/00325481.2021.1925562DOI Listing
May 2021

A nomogramic model based on clinical and laboratory parameters at admission for predicting the survival of COVID-19 patients.

BMC Infect Dis 2020 Nov 30;20(1):899. Epub 2020 Nov 30.

Department of Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.

Background: COVID-19 has become a major global threat. The present study aimed to develop a nomogram model to predict the survival of COVID-19 patients based on their clinical and laboratory data at admission.

Methods: COVID-19 patients who were admitted at Hankou Hospital and Huoshenshan Hospital in Wuhan, China from January 12, 2020 to March 20, 2020, whose outcome during the hospitalization was known, were retrospectively reviewed. The categorical variables were compared using Pearson's χ-test or Fisher's exact test, and continuous variables were analyzed using Student's t-test or Mann Whitney U-test, as appropriate. Then, variables with a P-value of ≤0.1 were included in the log-binomial model, and merely these independent risk factors were used to establish the nomogram model. The discrimination of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC), and internally verified using the Bootstrap method.

Results: A total of 262 patients (134 surviving and 128 non-surviving patients) were included in the analysis. Seven variables, which included age (relative risk [RR]: 0.905, 95% confidence interval [CI]: 0.868-0.944; P < 0.001), chronic heart disease (CHD, RR: 0.045, 95% CI: 0.0097-0.205; P < 0.001, the percentage of lymphocytes (Lym%, RR: 1.125, 95% CI: 1.041-1.216; P = 0.0029), platelets (RR: 1.008, 95% CI: 1.003-1.012; P = 0.001), C-reaction protein (RR: 0.982, 95% CI: 0.973-0.991; P < 0.001), lactate dehydrogenase (LDH, RR: 0.993, 95% CI: 0.990-0.997; P < 0.001) and D-dimer (RR: 0.734, 95% CI: 0.617-0.879; P < 0.001), were identified as the independent risk factors. The nomogram model based on these factors exhibited a good discrimination, with an AUC of 0.948 (95% CI: 0.923-0.973).

Conclusions: A nomogram based on age, CHD, Lym%, platelets, C-reaction protein, LDH and D-dimer was established to accurately predict the prognosis of COVID-19 patients. This can be used as an alerting tool for clinicians to take early intervention measures, when necessary.
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http://dx.doi.org/10.1186/s12879-020-05614-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702207PMC
November 2020

Experimentally Induced Sepsis Causes Extensive Hypomyelination in the Prefrontal Cortex and Hippocampus in Neonatal Rats.

Neuromolecular Med 2020 09 7;22(3):420-436. Epub 2020 Jul 7.

Department of Critical Care and Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.

Neonatal sepsis is associated with cognitive deficit in the later life. Axonal myelination plays a pivotal role in neurotransmission and formation of learning and memory. This study aimed to explore if systemic lipopolysaccharide (LPS) injection would induce hypomyelination in the prefrontal cortex and hippocampus in developing septic neonatal rats. Sprague-Dawley rats (1-day old) were injected with LPS (1 mg/kg) intraperitoneally. By electron microscopy, axonal hypomyelination was evident in the subcortical white matter and hippocampus. The expression of myelin proteins including CNPase, MBP, PLP and MAG was downregulated in both areas of the brain at 7, 14 and 28 days after LPS injection. The frequency of MBP and PLP-positive oligodendrocyte was significantly reduced using in situ hybridization in the cerebral cortex and hippocampus at the corresponding time points after LPS injection, whereas the expression of NG2 and PDGFRα was noticeably increased. In tandem with this was reduction of Olig1 and Olig2 expressions which are involved in differentiation/maturation of OPCs. Expression of NFL, NFM, and NFH was significantly downregulated, indicating that axon development was disrupted after LPS injection. Morris Water Maze behavioral test, Open field test, Rotarod test, and Pole test were used to evaluate neurological behaviors of 28 days rats. The rats in the LPS group showed the impairment of motor coordination, balance, memory, and learning ability and represented bradykinesia and anxiety-like behavior. The present results suggest that following systemic LPS injection, differentiation/maturation of OPCs was affected which may be attributed to the inhibition of transcription factors Olig1 and Olig2 expression resulting in impairment to axonal development. It is suggested that this would ultimately lead to axonal hypomyelination in the prefrontal cortex and hippocampus, which may be associated with neurological deficits in later life.
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http://dx.doi.org/10.1007/s12017-020-08602-6DOI Listing
September 2020

A study on infectivity of asymptomatic SARS-CoV-2 carriers.

Respir Med 2020 08 13;169:106026. Epub 2020 May 13.

Department of Respiratory and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Geriatrics Institute, Guangzhou, 510080, China. Electronic address:

Background: An ongoing outbreak of coronavirus disease 2019 (COVID-19) has spread around the world. It is debatable whether asymptomatic COVID-19 virus carriers are contagious. We report here a case of the asymptomatic patient and present clinical characteristics of 455 contacts, which aims to study the infectivity of asymptomatic carriers.

Material And Methods: 455 contacts who were exposed to the asymptomatic COVID-19 virus carrier became the subjects of our research. They were divided into three groups: 35 patients, 196 family members and 224 hospital staffs. We extracted their epidemiological information, clinical records, auxiliary examination results and therapeutic schedules.

Results: The median contact time for patients was four days and that for family members was five days. Cardiovascular disease accounted for 25% among original diseases of patients. Apart from hospital staffs, both patients and family members were isolated medically. During the quarantine, seven patients plus one family member appeared new respiratory symptoms, where fever was the most common one. The blood counts in most contacts were within a normal range. All CT images showed no sign of COVID-19 infection. No severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections was detected in 455 contacts by nucleic acid test.

Conclusion: In summary, all the 455 contacts were excluded from SARS-CoV-2 infection and we conclude that the infectivity of some asymptomatic SARS-CoV-2 carriers might be weak.
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http://dx.doi.org/10.1016/j.rmed.2020.106026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219423PMC
August 2020

Hypercapnia Exacerbates the Blood-Brain Barrier Disruption Via Promoting HIF-1a Nuclear Translocation in the Astrocytes of the Hippocampus: Implication in Further Cognitive Impairment in Hypoxemic Adult Rats.

Neurochem Res 2020 Jul 23;45(7):1674-1689. Epub 2020 Apr 23.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.

Hypercapnia in combination with hypoxemia is usually present in severe respiratory disease in the intensive care unit (ICU) and can lead to more severe cognitive dysfunction. Increasing evidence has indicated that the compromised blood-brain barrier (BBB) in the hippocampus in hypoxemia conditions can result in cognitive dysfunction. However, the role and underlying mechanism of hypercapnia in the BBB disruption remains poorly known. A rat model of hypercapnia was first established in this study by intubation and mechanical ventilation with a small-animal ventilator. After this, the cognitive function of the experimental rats was assessed by the Morris water maze test. The BBB permeability was evaluated by the Evans Blue (EB) test and brain water content (BWC). Western blot analysis was carried out to detect the protein expressions of total and nuclear hypoxia-inducible factor-1α (HIF-1α), matrixmetalloproteinase-9 (MMP-9) and Aquaporins-4 (AQP-4) in the hippocampus tissue. Double immunofluorescence further verified the protein expression of different biomarkers was localized in the astrocytes of the hippocampus. Hypercapnia alone did not disrupt the BBB, but it could further enhance the BBB permeability in hypoxemia. Concomitantly, up-regulation of nuclear HIF-1α, AQP-4, MMP-9 protein expression along with increased degradation of the occludin and claudin-5 proteins was found in the hypercapnia rat model, while the total HIF-1α remained unchanged. Interestingly, these changes were independent of the acidosis induced by hypercapnia. Of note, after premedication of 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α nuclear translocation), the disrupted BBB could be restored resulting in improvement of the cognitive impairment. Meanwhile, accumulation of nuclear HIF-1α, protein expression of AQP-4 and MMP-9 and protein degradation of the occludin and claudin-5 were decreased. Thus, our study demonstrated that hypercapnia can further disrupt the BBB through promoting HIF-1α nuclear translocation and up-regulation of AQP-4 and MMP-9 in hypoxemia. It is therefore suggested that the cascade of hypercapnia-induced nuclear HIF-1α protein translocation in hypoxia-activated astrocytes may be a potential target for ameliorating cognitive impairment.
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http://dx.doi.org/10.1007/s11064-020-03038-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224048PMC
July 2020

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β-catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide.

Brain Pathol 2020 05 6;30(3):495-514. Epub 2019 Nov 6.

Department of Critical Care and Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.

Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/β-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2 oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP and MBP cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2 cells and decreased number of CC1 cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/β-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/β-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination.
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http://dx.doi.org/10.1111/bpa.12798DOI Listing
May 2020

Hypertonic saline downregulates endothelial cell-derived VEGF expression and reduces blood-brain barrier permeability induced by cerebral ischaemia via the VEGFR2/eNOS pathway.

Int J Mol Med 2019 Sep 2;44(3):1078-1090. Epub 2019 Jul 2.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.

The aim of the present study was to explore the possible mechanisms by which hypertonic saline (HS) effectively ameliorates cerebral oedema via the vascular endothelial growth factor receptor 2 (VEGFR2)‑mediated endothelial nitric oxide synthase (eNOS) pathway of endothelial cells in rats. A middle cerebral artery occlusion (MCAO) model in Sprague‑Dawley rats and an oxygen‑glucose deprivation (OGD) model in cells were used in the present study. Evans blue (EB) staining and a horseradish peroxidase flux assay were performed to evaluate the protective effect of 10% HS on the blood‑brain barrier (BBB). The expression levels of vascular endothelial growth factor (VEGF), VEGFR2, zonula occludens 1 (ZO1) and occludin were quantified. The results demonstrated that 10% HS effectively reduced EB extravasation in the peri‑ischaemic brain tissue. At 24 h after MCAO, the protein expression levels of VEGF and VEGFR2 in the peri‑ischaemic brain tissue were downregulated following treatment with 10% HS. In vitro experiments demonstrated that the permeability of a monolayer endothelial cell barrier was decreased significantly following HS treatment. In addition, VEGF and VEGFR2 protein expression levels were increased in endothelial cells under hypoxic conditions, but that effect was suppressed by HS treatment. Furthermore, HS inhibited the downregulation of ZO1 and occludin effectively, possibly through the VEGFR2/phospholipase C γ1 (PLCγ1)/eNOS signalling pathway. In conclusion, 10% HS may alleviate cerebral oedema through reducing ischaemia‑induced BBB permeability, as a consequence of inhibiting VEGFR2/PLCγ1/eNOS‑mediated downregulation of ZO1 and occludin.
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http://dx.doi.org/10.3892/ijmm.2019.4262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657973PMC
September 2019

Synaptic structure and alterations in the hippocampus in neonatal rats exposed to lipopolysaccharide.

Neurosci Lett 2019 09 6;709:134364. Epub 2019 Jul 6.

Department of Critical Care and Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China. Electronic address:

Synaptic structure integrity plays a key role in learning and memory. Previous studies have shown that there is cognitive dysfunction in septic neonates in later life. In this study, intraperitoneal injection of lipopolysaccharide (LPS) in the developing rats was used as a sepsis model to determine whether hippocampal synapses would be affected. Expression of synaptophysin (Syn), synaptosomal associated protein of 25 kD (SNAP-25), and N-methyl d-aspartate receptor (NMDAR) in the hippocampus in septic brain were significantly reduced. Consistent with this, the number of dendritic spines associated with the pyramidal neurons in the CA1 region of hippocampus at 28d after LPS administration was decreased. Additionally, the number of synapse and synaptic vesicles were reduced and appeared swollen. The number of neurons in the CA1 and CA3 of hippocampus at 14, and 28d after LPS injection remained unchanged. Coupled with the above was upregulated expression of interleukin-1β (IL-1β), IL-1 receptor 1 (IL-R1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) at 1-3d after LPS injection. IL-1β expression was specifically detected in activated microglia. The plasma corticosterone (CORT) concentration in the LPS treatment rats was increased; but the glucocorticoid receptor (GR) expression in the hippocampus was decreased. We conclude that LPS injection in neonatal rats can cause synaptic disruption in the hippocampus which may be attributed to inflammatory response due to excess production of proinflammatory cytokines e.g., IL-1β derived from activated microglia. The significance of increased plasma CORT concentration and decreased GR expression in the hippocampus is discussed.
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http://dx.doi.org/10.1016/j.neulet.2019.134364DOI Listing
September 2019

Interleukin-1β Disturbs the Proliferation and Differentiation of Neural Precursor Cells in the Hippocampus via Activation of Notch Signaling in Postnatal Rats Exposed to Lipopolysaccharide.

ACS Chem Neurosci 2019 05 20;10(5):2560-2575. Epub 2019 Mar 20.

Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China.

Infectious exposure during the perinatal period may predispose to permanent neurological disorders in later life. Here we investigated whether changes in interleukin-1β (IL-1β) are associated with cognitive dysfunction in later life of septic neonatal rats through suppression of neurogenesis in the hippocampus. Sprague-Dawley rats (1-day old) administered lipopolysaccharide (LPS) showed upregulated expression of IL-1β and IL-1 receptors in the hippocampus. At 28 days of age, rats showed longer escape latencies and decreased numbers of crossings after LPS administration. This was coupled with increased numbers of glial fibrillary acidic protein positive (GFAP) astrocytes and decreased numbers of neuronal nuclei positive (NeuN) cells. The numbers of sex-determining region Y-box 2 positive (SOX2) and doublecortin positive (DCX) cells were decreased at 1 and 3 days but was increased at 7 and 14 days. The proliferation of SOX2 cells was inhibited at 1 and 3 days but increased at 7 and 14 days. In vitro IL-1β administration suppressed the proliferation of neural progenitor cells (NPCs) in neurospheres derived from the hippocampus. GFAP expression was upregulated in differentiated NPCs treated with IL-1β for 4 days, but expression of DCX and microtubule associated protein-2 (MAP2) was decreased. Remarkably, the Notch signaling pathway involved in antineurogenic and progliogenic differentiation of NPCs was activated after IL-1β administration. The results show that following LPS injection in neonatal rats, microglia were activated and generated excess amounts of IL-1β in the hippocampus. It is suggested that this might have contributed to inhibiting neurogenesis but promoting gliogenesis of NPCs via activation of the Notch signaling pathway and maybe one of the causes for cognitive dysfunction in septic neonatal rats in later life.
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http://dx.doi.org/10.1021/acschemneuro.9b00051DOI Listing
May 2019

Long non‑coding RNA DILC is involved in sepsis by modulating the signaling pathway of the interleukin‑6/signal transducer and activator of transcription 3/Toll‑like receptor 4 axis.

Mol Med Rep 2018 Dec 16;18(6):5775-5783. Epub 2018 Oct 16.

Department of Emergency and Critical Care Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.

Sepsis is characterized by systemic inflammatory responses. In the present study, the role of deleted in liver cancer 1 (DILC), interleukin (IL)‑6, signal transducer and activator of transcription 3 (STAT3), and Toll‑like receptor 4 (TLR4) in the pathogenesis of sepsis was investigated. Reverse transcription‑quantitative polymerase chain reaction analysis and western blotting were performed to evaluate the effects of lipopolysaccharide (LPS) on the expression of DILC, IL‑6, STAT3, and TLR4, in addition to the effects of DILC and IL‑6 on the synthesis of tumor necrosis factor (TNF‑α), chemokine ligand 5 (CCL5), E‑selectin and C‑X‑C motif chemokine receptor 1 (CXCR1). In addition, the regulatory association between DILC, IL‑6, STAT3 and TLR4 was investigated. LPS reduced the expression level of DILC, and enhanced the expression of IL‑6, STAT3 and TLR4. DILC directly and negatively regulated the synthesis of IL‑6, as demonstrated by the markedly decreased luciferase activity in cells transfected with a wild‑type DILC plasmid. On the other hand, compared with the scramble control, DILC and IL‑6 small interfering (si)RNAs significantly suppressed the expression of IL‑6, STAT3 and TLR4. In addition, DILC siRNA enhanced the expression of IL‑6, STAT3 and TLR4, whereas the expression levels of TNF‑α, CCL5, E‑selectin and CXCR1 in LPS‑treated THP‑1 cells were downregulated following transfection with DILC and IL‑6 siRNAs. In patients with sepsis, DILC expression was inhibited, although the expression levels of IL‑6, STAT3 and TLR4 were upregulated. In addition, the expression levels of TNF‑α, CCL5, E‑selectin and CXCR1 in patients with sepsis were higher compared with normal subjects. Therefore, DILC may mediate the crosstalk between the cascades of IL‑6/STAT3 and TNF‑α signaling, indicating that DILC may act as a prognostic biomarker of sepsis, and may serve as a potential therapeutic target for the treatment of sepsis.
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http://dx.doi.org/10.3892/mmr.2018.9559DOI Listing
December 2018

Evaluation of a combination "lymphocyte apoptosis model" to predict survival of sepsis patients in an intensive care unit.

BMC Anesthesiol 2018 07 18;18(1):89. Epub 2018 Jul 18.

The Second School of Clinical Medicine, Southern Medical University, 1063 Shatai Nan road, Guangzhou, 510515, China.

Background: A major challenge in sepsis intervention is unclear risk stratification. We postulated that a panel of biomarkers of lymphocyte apoptosis and immune function, termed the "lymphocyte apoptosis model," would be an effective tool for predicting 28-day survival for sepsis patients.

Methods: A total of 52 consecutive sepsis patients were enrolled. Peripheral blood samples were collected on day 1 of admission for quantification of biomarkers of lymphocyte apoptosis and immune function, including lymphocyte count, lymphocyte apoptotic percentage, expression on monocyte HLA-DR, CD4/CD8 T cell ratio, T helper type 1 to type 2 ratio (Th1/Th2), cytochrome c levels, and various proinflammatory cytokine levels. Sepsis severity was classified using Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Survival was assessed at 28 days.

Results: Compared with survivors, non-survivors had significantly higher lymphocyte apoptotic percentages and plasma cytochrome c levels and significantly lower lymphocyte counts, Th1/Th2 ratios, and HLA-DR expression on day 1 of admission. Multivariate analysis identified cytochrome c levels (odds ratio [OR]1.829, p = 0.025), lymphocyte apoptotic percentage (OR 1.103, p = 0.028), lymphocyte count (OR 0.150, p = 0.047), and HLA-DR expression (OR 0.923, p = 0.021) as independent predictors of 28-day mortality. A logistic regression equation incorporating the independent risk factors predicted 28-day mortality with greater accuracy than did the APACHE II score or single components biomarkers.

Conclusions: The "lymphocyte apoptosis model" may be useful for risk stratification and predicting prognosis of sepsis patients.
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http://dx.doi.org/10.1186/s12871-018-0535-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052570PMC
July 2018

Novel β-lactam/β-lactamase inhibitors versus alternative antibiotics for the treatment of complicated intra-abdominal infection and complicated urinary tract infection: a meta-analysis of randomized controlled trials.

Expert Rev Anti Infect Ther 2018 02 24;16(2):111-120. Epub 2018 Jan 24.

a Department of Critical Care Medicine and Emergency , Guangdong General Hospital, Guangdong Academy of Medical Sciences , Guangzhou , Guangdong , PR China.

Introduction: The aim of this study is to compare the efficacy and safety of novelBL/BLIs with alternative antibiotics for the treatment of cIAI and cUTI. Area covered: We performed a systematic review and meta-analysis of all randomized controlled trials comparing novel BL/BLIs with other antibiotics for the treatment of cIAI and cUTI. The primary outcome included clinical and microbiological treatment success. Expert commentary: We found that novel BL/BLIs obtained a similar clinical outcome with other antibiotics in CE population (OR = 1.07, 95%CI = (0.80, 1.44), P = 0.64). However, novel BL/BLIs had better clinical treatment success in the cUTI subgroup (OR = 2.14, 95%CI = (1.06, 4.31), P = 0.03). Furthermore, novel BL/BLIs achieved significant microbiological treatment success in patie nts with cUTI (OR = 1.70, 95%CI = (1.29, 2.25), P  =  0.0002) and had higher eradication rates for Gram-negative pathogens (OR = 1.82, 95%CI = (1.26, 2.64), P = 0.001) including E.coli and K.pneumoniae. No difference was observed concerning the incidence of mortality and adverse events between the two groups. Therefore, we concluded that novel BL/BLIs are not inferior to other available antibiotics for the treatment of cIAI, and they have advantages in patients with cUTI. Simultaneously, they are sensitive to Gram-negative pathogens, especially for E.coli and K.pneumoniae.
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http://dx.doi.org/10.1080/14787210.2018.1429912DOI Listing
February 2018

Magnetic resonance spectroscopy for assessment of brain injury in the rat model of sepsis.

Exp Ther Med 2017 Nov 25;14(5):4118-4124. Epub 2017 Aug 25.

Department of Acute Critical Care Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.

The diagnostic value of magnetic resonance spectroscopy (MRS), T2-weighted imaging (T2WI) and serum markers of brain injury in a rat model of sepsis were investigated. Rats were randomly divided into the control group and 6, 12 and 24 h after lipopolysaccharide-injection groups. Brain morphology and metabolism were assessed with T2WI magnetic resonance imaging (MRI) and MRS. Serum and brain tissue samples were then collected to examine the concentrations of neuron-specific enolase (NSE) and S100-β protein. Brain T2WI showed no differences between the groups. N-acetylaspartate/choline (NAA/Cr) ratio measured by MRS showed different degrees of decrease in the sepsis groups, and serum NSE and S100-β concentrations were increased compared with the control group. Apoptosis rates were measured in the right hippocampal area, and there were statistically significant differences between the indicated groups and the control group (p<0.05). The correlation between apoptosis rate and NAA/Cr ratio was closer than that between apoptosis rate and NSE or S100-β (-0.925 vs. 0.434 vs. 0.517, respectively). In conclusion, MRS is a sensitive, non-invasive method to investigate complications of brain injury in septic rats, which may be utilized for the early diagnosis of brain injury caused by sepsis.
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http://dx.doi.org/10.3892/etm.2017.5034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647722PMC
November 2017

The Incidence, Risk Factors and Outcomes of Postoperative Acute Kidney Injury in Neurosurgical Critically Ill Patients.

Sci Rep 2017 06 26;7(1):4245. Epub 2017 Jun 26.

Department of Critical Care Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong Province, P.R. China.

We investigated the incidence, perioperative risk factors, and outcomes of postoperative acute kidney injury (AKI) in neurosurgical critically ill patients. A prospective multicenter cohort study was conducted, enrolling adult patients who underwent neurosurgical procedure and admitted to the neurosurgical intensive care units (ICU). Postoperative AKI was diagnosed within 7 days after surgery based on the Kidney Disease Improving Global Outcomes criteria. Of 624 enrolled patients, postoperative AKI occurred in 84 patients. AKI was associated with increased rates of ICU and in-hospital mortality, postoperative renal replacement therapy, postoperative tracheotomy, and postoperative tracheal reintubation. Patients who developed AKI had higher total ICU costs, prolonged length of hospital and ICU stay, and longer duration of postoperative mechanical ventilation. Multivariate analysis identified postoperative reoperation (adjusted odds ratio [OR] 5.70 [95% CI, 1.61-20.14]), postoperative concentration of serum cystatin C (adjusted OR 4.53 [95% CI, 1.98-10.39]), use of mannitol during operation (adjusted OR 1.97 [95% CI, 1.13-3.43]), postoperative APACHE II score (adjusted OR 1.11 [95% CI, 1.06-1.16]), and intraoperative estimated blood loss (adjusted OR 1.04 [95% CI, 1.00-1.08]) as independent risk factors for postoperative AKI. Postoperative AKI in neurosurgical critically ill cohort is prevalent and associated with adverse in-hospital outcomes.
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http://dx.doi.org/10.1038/s41598-017-04627-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484679PMC
June 2017

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats.

J Neuroinflammation 2017 03 14;14(1):52. Epub 2017 Mar 14.

Southern Medical University, Guangzhou, 510515, People's Republic of China.

Background: Axon development plays a pivotal role in the formation of synapse, nodes of Ranvier, and myelin sheath. Interleukin-1β (IL-1β) produced by microglia may cause myelination disturbances through suppression of oligodendrocyte progenitor cell maturation in the septic neonatal rats. Here, we explored if a microglia-derived IL-1β would disturb axon development in the corpus callosum (CC) following lipopolysaccharide (LPS) administration, and if so, whether it is associated with disorder of synapse formation in the cerebral cortex and node of Ranvier.

Methods: Sprague-Dawley rats (1-day old) in the septic model group were intraperitoneally administrated with lipopolysaccharide (1 mg/kg) and then sacrificed for detection of IL-1β, interleukin-1 receptor (IL-1R), neurofilament-68, neurofilament-160, and neurofilament-200, proteolipid, synaptophysin, and postsynaptic density 95 (PSD95) expression by western blotting and immunofluorescence. Electron microscopy was conducted to observe alterations of axonal myelin sheath and synapses in the cortex, and proteolipid expression was assessed using in situ hybridization. The effect of IL-1β on neurofilament and synaptophysin expression in primary neuron cultures was determined by western blotting and immunofluorescence. P38-MAPK signaling pathway was investigated to determine whether it was involved in the inhibition of IL-1β on neurofilament and synaptophysin expression.

Results: In 1-day old septic rats, IL-1β expression was increased in microglia coupled with upregulated expression of IL-1R on the axons. The expression of neurofilament-68, neurofilament-160, and neurofilament-200 (NFL, NFM, NFH) and proteolipid (PLP) was markedly reduced in the CC at 7, 14, and 28 days after LPS administration. Simultaneously, cortical synapses and mature oligodendrocytes were significantly reduced. By electron microscopy, some axons showed smaller diameter and thinner myelin sheath with damaged ultrastructure of node of Ranvier compared with the control rats. In the cerebral cortex of LPS-injected rats, some axo-dendritic synapses appeared abnormal looking as manifested by the presence of swollen and clumping of synaptic vesicles near the presynaptic membrane. In primary cultured neurons incubated with IL-1β, expression of NFL, NFM, and synaptophysin was significantly downregulated. Furthermore, p38-MAPK signaling pathway was implicated in disorder of axon development and synaptic deficit caused by IL-1β treatment.

Conclusions: The present results suggest that microglia-derived IL-1β might suppress axon development through activation of p38-MAPK signaling pathway that would contribute to formation disorder of cortical synapses and node of Ranvier following LPS exposure.
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http://dx.doi.org/10.1186/s12974-017-0805-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348817PMC
March 2017

Hypertonic saline alleviates experimentally induced cerebral oedema through suppression of vascular endothelial growth factor and its receptor VEGFR2 expression in astrocytes.

BMC Neurosci 2016 10 13;17(1):64. Epub 2016 Oct 13.

Department of Emergency and Critical Care Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.

Background: Cerebral oedema is closely related to the permeability of blood-brain barrier, vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) all of which are important blood-brain barrier (BBB) permeability regulatory factors. Zonula occludens 1 (ZO-1) and claudin-5 are also the key components of BBB. Hypertonic saline is widely used to alleviate cerebral oedema. This study aimed to explore the possible mechanisms underlying hypertonic saline that ameliorates cerebral oedema effectively.

Methods: Middle cerebral artery occlusion (MCAO) model in Sprague-Dawley (SD) rats and of oxygen-glucose deprivation model in primary astrocytes were used in this study. The brain water content (BWC) was used to assess the effect of 10 % HS on cerebral oedema. The assessment of Evans blue (EB) extravasation was performed to evaluate the protective effect of 10 % HS on blood-brain barrier. The quantification of VEGF, VEGFR2, ZO-1 and claudin-5 was used to illustrate the mechanism of 10 % HS ameliorating cerebral oedema.

Results: BWC was analysed by wet-to-dry ratios in the ischemic hemisphere of SD rats; it was significantly decreased after 10 % HS treatment (P < 0.05). We also investigated the blood-brain barrier protective effect by 10 % HS which reduced EB extravasation effectively in the peri-ischemic brain tissue. In parallel to the above notably at 24 h following MCAO, mRNA and protein expression of VEGF and VEGFR2 in the peri-ischemic brain tissue was down-regulated after 10 % HS treatment (P < 0.05). Along with this, in vitro studies showed increased VEGF and VEGFR2 mRNA and protein expression in primary astrocytes under hypoxic condition (P < 0.05), but it was suppressed after HS treatment (P < 0.05). In addition, HS inhibited the down-regulation of ZO-1, claudin-5 effectively.

Conclusions: The results suggest that 10 % HS could alleviate cerebral oedema possibly through reducing the ischemia induced BBB permeability as a consequence of inhibiting VEGF-VEGFR2-mediated down-regulation of ZO-1, claudin-5.
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http://dx.doi.org/10.1186/s12868-016-0299-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062881PMC
October 2016

[Effect of axonal developmental disorders in the corpus callosum on the neurological function after birth in septic neonatal rats].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2016 Aug;28(8):683-7

Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China (Deng YY, Han QP, Chen MM, Zeng HK); Department of Rheumatology, the First Affiliated Hospital, Shantou University Medical College, Shantou 515000, Guangdong, China (Shen FC). Corresponding author: Deng Yiyu, Email:

Objective: To observe the axonal development in the corpus callosum of septic neonatal rats, and its effect on the neurological function after birth.

Methods: Forty-eight 1-day-old Sprague-Dawley (SD) rats were randomly divided into two groups: control group and sepsis group, with 24 rats in each group. The rat model of sepsis was reproduced by intraperitoneal injection of 1 mg/kg lipopolysaccharide (LPS), and the rats in control group were injected with an equal volume of phosphate buffered saline (PBS). The corpus callosum in brain was harvested at 7, 14, and 28 days after model reproduction, and double immunofluorescence staining and Western Blot were used to observe the expression of neurofilament heavy chain (NFH), neurofilament medium chain (NFM) and neurofilament light chain (NFL) in the corpus callosum. The morphology and number of axon were observed in the corpus callosum of rats at 28 days using electron microscopy. The number of myelin basic protein (MBP) positive cells in the corpus callosum of rats was determined by in situ hybridization.

Results: The immunofluorescence intensities of NFH, NFM, and NFL in the corpus callosum of rats at 7, 14, and 28 days after model reproduction in sepsis group were significantly lower than those of control group. In addition, it was revealed by Western Blot results that the protein expression levels of NFH, NFM, and NFL in sepsis group were significantly lower than those of control group [NFH (gray value): 0.16±0.03 vs. 0.34±0.04 at 7 days, 1.75±0.11 vs. 2.42±0.17 at 14 days, 3.39±0.25 vs. 5.11±0.23 at 28 days; NFM (gray value): 0.34±0.04 vs. 0.53±0.04 at 7 days, 0.74±0.04 vs. 1.12±0.07 at 14 days, 0.92±0.06 vs. 1.52±0.07 at 28 days; NFL (gray value): 0.12±0.02 vs. 0.26±0.14 at 7 days, 0.32±0.03 vs. 0.81±0.04 at 14 days, 0.85±0.08 vs. 1.81±0.05 at 28 days; P < 0.05 or P <0.01]. In the control group, an obvious myelination was found in the corpus callosum of rats on the 28th day after the birth, and the nodes of Ranvier were clearly distinguishable, with intact structure and smooth edges. The number of myelinated axons was reduced and the nodes of Ranvier were impaired in the corpus callosum of rats at 28 days after LPS injection. The expression of MBP in the corpus callosum of rats at 28 days after LPS injection was obviously decreased compared with control group (cells/LP: 23.67±3.21 vs. 35.00±3.61, P < 0.01).

Conclusions: The axonal development in the corpus callosum of septic neonatal rats on the 28th day after the birth was impaired, and lead to reduced myelination and further deterioration of neurological function.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2016.08.003DOI Listing
August 2016

[Microbial characteristics in culture-positive sepsis and risk factors of polymicrobial infection in ICU].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2015 Sep;27(9):718-23

Objective: To investigate the clinical characteristics and pathogenic microorganisms in culture-positive sepsis, to identify its risk factors, and evaluate the prognosis on polymicrobial infection in intensive care unit (ICU).

Methods: A descriptive retrospective study was conducted. Clinical data of patients aged ≥ 18 years, diagnosed as culture-positive sepsis, and admitted to six ICUs of Guangdong General Hospital from October 12th, 2012 to December 1st, 2014 were enrolled. Based on the number of isolated pathogens, patients were divided into polymicrobial infection group (≥ two pathogens) and monomicrobial infection group (one pathogen) to investigate the clinical characteristics of patients with culture-positive sepsis and the causative pathogens. Multiple logistic regression was conducted to identify the risk factors for polymicrobial infection. Kaplan-Meier curve was plotted to analyze a 90-day survival rate from the onset of positive blood culture.

Results: 299 patients with positive blood culture were enrolled. A total of 450 strains of pathogens were isolated including 246 gram-positive cocci (54.67%), 167 gram-negative bacilli (37.11%) and 37 fungi (8.22%). Ninety-one patients had polymicrobial infection, and 208 with monomicrobial infection. Compared with monomicrobial infection group, patients suffering from polymicrobial infection had more advanced age (years: 73.19 ± 18.02 vs. 60.83 ± 18.06, t = -5.447, P = 0.000), also with higher incidence of cerebrovascular diseases [39.56% (36/91) vs. 17.79% (37/208), χ2 = 16.261, P = 0.000] or chronic renal insufficiency [15.38% (14/91) vs. 7.21% (15/208), χ2 = 4.828, P = 0.028], higher incidence of recent hospital stay (≥ 2 days) within 90 days [73.63% (67/91) vs. 61.54% (128/208), χ2 = 4.078, P = 0.043], longer mechanical ventilation duration [days: 4 (0, 17) vs. 1 (0, 6), U = 7673.000, P = 0.006], longer length of hospital stay before blood was drawn for culture [days: 21 (7, 40) vs. 9 (3, 17), U = 6 441.500, P = 0.006], and higher incidence of pre-admission intravenous use of antibiotics [84.62% (77/91) vs. 66.83% (139/208), χ2 = 9.989, P = 0.002]. Multiple logistic regression analysis showed that advanced age [odd ratio (OR) = 1.032, 95% confidential interval (95% CI) = 1.015-1.050, P = 0.000], cerebrovascular diseases (OR = 2.247, 95%CI = 1.234-4.090, P = 0.008), prolonged mechanical ventilation (OR = 1.041, 95% CI = 1.014-1.069, P = 0.003), and recent hospital stay (≥ 2 days) within 90 days (OR = 1.968, 95%CI = 1.079-3.592, P = 0.027) were the independent risk factors for polymicrobial infection. In the polymicrobial infection group, the length of ICU stay [days: 46 (22, 77) vs. 13 (7, 22), U = 3 148.000, P = 0.000] and hospital stay [days: 81 (47, 118) vs. 28 (17, 46), U = 3 620.000, P = 0.000] were significantly longer, and the ICU mortality [65.93% (60/91) vs. 43.75% (91/208), χ2 = 12.463, P = 0.000 ] and hospital mortality [68.13% (62/91) vs. 45.67% (95/208), χ2 = 12.804, P = 0.000] were significantly higher, and on the other hand the 90-day survival rate was significantly lower than that in the monomicrobial infection group (χ2 = 8.513, P = 0.004).

Conclusions: The most common pathogen of ICU sepsis is gram-positive cocci. Independent risk factors for polymicrobial infections were found to be advanced age, occurrence of cerebrovascular disease, prolonged mechanical ventilation, and recent hospitalization. Polymicrobial infection is associated with longer length of ICU and hospital stay, as well as higher mortality.
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September 2015

IL-1β induces hypomyelination in the periventricular white matter through inhibition of oligodendrocyte progenitor cell maturation via FYN/MEK/ERK signaling pathway in septic neonatal rats.

Glia 2016 Apr 17;64(4):583-602. Epub 2015 Dec 17.

Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.

Neuroinflammation elicited by microglia plays a key role in periventricular white matter (PWM) damage (PWMD) induced by infectious exposure. This study aimed to determine if microglia-derived interleukin-1β (IL-1β) would induce hypomyelination through suppression of maturation of oligodendrocyte progenitor cells (OPCs) in the developing PWM. Sprague-Dawley rats (1-day old) were injected with lipopolysaccharide (LPS) (1 mg/kg) intraperitoneally, following which upregulated expression of IL-1β and IL-1 receptor 1 (IL-1R1 ) was observed. This was coupled with enhanced apoptosis and suppressed proliferation of OPCs in the PWM. The number of PDGFR-α and NG2-positive OPCs was significantly decreased in the PWM at 24 h and 3 days after injection of LPS, whereas it was increased at 14 days and 28 days. The protein expression of Olig1, Olig2, and Nkx2.2 was significantly reduced, and mRNA expression of Tcf4 and Axin2 was upregulated in the developing PWM after LPS injection. The expression of myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3"-phosphodiesterase (CNPase) was downregulated in the PWM at 14 days and 28 days after LPS injection; this was linked to reduction of the proportion of myelinated axons and thinner myelin sheath as revealed by electron microscopy. Primary cultured OPCs treated with IL-1β showed the failure of maturation and proliferation. Furthermore, FYN/MEK/ERK signaling pathway was involved in suppression of maturation of primary OPCs induced by IL-1β administration. Our results suggest that following LPS injection, microglia are activated and produce IL-1β in the PWM in the neonatal rats. Excess IL-1β inhibits the maturation of OPCs via suppression of FYN/MEK/ERK phosphorylation thereby leading to axonal hypomyelination.
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http://dx.doi.org/10.1002/glia.22950DOI Listing
April 2016

Efficacy and safety of tigecycline for the treatment of severe infectious diseases: an updated meta-analysis of RCTs.

Int J Infect Dis 2015 Oct 15;39:25-33. Epub 2015 Aug 15.

Department of Critical Care Medicine and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China. Electronic address:

Objectives: To assess the efficacy and safety of tigecycline in comparison with other antimicrobial treatments for infectious diseases.

Design: Databases of PubMed, Embase and the Cochrane Library were searched through Feb. 2015. The reference lists of the initially identified articles and systemic review articles were manually searched. Randomized controlled trials assessing tigecycline and other antibiotics for infectious diseases in adult patients were included.

Results: Fifteen RCTs including 7689 cases were identified. We found that tigecycline was not as effective as the comparator agents for clinical treatment success (for the clinically evaluable population, odds ratio [OR] = 0.83, 95% confidence interval [CI] = (0.73, 0.96), P=0.01; for the clinically modified intent-to-treat (mITT) population, OR = 0.81, 95% CI = (0.72, 0.92), P=0.001). There was no significant difference in microbiological treatment success with lower eradication rate in tigecycline versus comparators (for the microbiologically evaluable population, OR = 0.94, 95% CI = (0.77, 1.16), P=0.56; for the microbiological mITT populations, OR = 0.91, 95% CI = (0.74, 1.11), P=0.35). Adverse events and all-cause mortality were more common in the tigecycline group.

Conclusions: Tigecycline is not as effective as other antibiotics with relatively more frequency of adverse events and higher mortality rate.
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http://dx.doi.org/10.1016/j.ijid.2015.08.009DOI Listing
October 2015

The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development.

Nat Commun 2015 Jan 21;6:6121. Epub 2015 Jan 21.

Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Mutations in GPR56, a member of the adhesion G protein-coupled receptor family, cause a human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Magnetic resonance imaging (MRI) of BFPP brains reveals myelination defects in addition to brain malformation. However, the cellular role of GPR56 in oligodendrocyte development remains unknown. Here, we demonstrate that loss of Gpr56 leads to hypomyelination of the central nervous system in mice. GPR56 levels are abundant throughout early stages of oligodendrocyte development, but are downregulated in myelinating oligodendrocytes. Gpr56-knockout mice manifest with decreased oligodendrocyte precursor cell (OPC) proliferation and diminished levels of active RhoA, leading to fewer mature oligodendrocytes and a reduced number of myelinated axons in the corpus callosum and optic nerves. Conditional ablation of Gpr56 in OPCs leads to a reduced number of mature oligodendrocytes as seen in constitutive knockout of Gpr56. Together, our data define GPR56 as a cell-autonomous regulator of oligodendrocyte development.
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http://dx.doi.org/10.1038/ncomms7121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302951PMC
January 2015

Astrocyte-derived proinflammatory cytokines induce hypomyelination in the periventricular white matter in the hypoxic neonatal brain.

PLoS One 2014 31;9(1):e87420. Epub 2014 Jan 31.

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD), a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL) loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC(+) OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM) and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC(+) oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909103PMC
October 2014

Disease-associated mutations prevent GPR56-collagen III interaction.

PLoS One 2012 4;7(1):e29818. Epub 2012 Jan 4.

Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251603PMC
May 2012

Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats.

Brain Pathol 2008 Jul 26;18(3):387-400. Epub 2008 Mar 26.

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Hypoxic injury in the perinatal period results in periventricular white matter (PWM) lesions with axonal damage and oligodendroglial loss. It also alters macrophage function by perpetuating expression of inflammatory mediators. Relevant to this is the preponderance of amoeboid microglial cells (AMC) characterized as active macrophages in the developing PWM. This study aimed to determine if AMC produce proinflammatory cytokines that may be linked to the oligodendroglial loss observed in hypoxic PWM damage (PWMD). Wistar rats (1 day old) were subjected to hypoxia, following which upregulated expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), TNF receptor 1 (TNF-R(1)) and IL-1 receptor 1 (IL-1R(1)) was observed. This was coupled with apoptosis and expression of TNF-R(1) and IL-1R(1) in oligodendrocytes. Primary cultured microglial cells subjected to hypoxia (3% oxygen, 5% CO(2) and 92% nitrogen) showed enhanced expression of TNF-alpha and IL-1beta. Furthermore, mitogen-activated protein (MAP) kinase signaling pathway was involved in the expression of TNF-alpha and IL-1beta in microglia subjected to hypoxia. Our results suggest that following a hypoxic insult, microglial cells in the neonatal rats produce inflammatory cytokines such as TNF-alpha and IL-1beta via MAP kinase signaling pathway. These cytokines are detrimental to oligodendrocytes resulting in PWM lesion.
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http://dx.doi.org/10.1111/j.1750-3639.2008.00138.xDOI Listing
July 2008