Publications by authors named "Xiaodan Ren"

24 Publications

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Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest.

Mol Neurobiol 2022 Jan 14. Epub 2022 Jan 14.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO administrated during CPR could achieve therapeutic serum magnesium levels within 15 min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107 mg/kg, 215 mg/kg, or 430 mg/kg MgSO IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15 min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO during CPR had no effect on ROSC rate (p > 0.05). IM MgSO treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO during CPR achieves up to fourfold baseline serum magnesium levels within 15 min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.
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http://dx.doi.org/10.1007/s12035-021-02645-xDOI Listing
January 2022

Traditional Chinese medicine formula Xiaoqinglong decoction for cough caused by COVID-19: A protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2020 Nov;99(48):e23261

Beibei Traditional Chinese Medical Hospital, Chongqing, China.

Background: Assessing the effectiveness and safety of Traditional Chinese medicine formula Xiaoqinglong decoction for cough caused by COVID-19 is the main purpose of this systematic review protocol.

Methods: The following electronic databases will be searched from their respective inception dates to October 1, 2020: PubMed, MEDLINE, the Cochrane Library, Embase, WorldSciNet, Ovid, the Allied and Complementary Medicine Database, the Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), the Wanfang Database, and the China Biology Medicine Disc. All published randomized controlled trials in English or Chinese related to Traditional Chinese medicine formula Xiaoqinglong decoction for cough caused by COVID-19 will be included. The primary outcome is the time and rate of appearance of coughing. The secondary outcomes are the length of hospital stay. Two reviewers will conduct the study selection, data extraction, and assessment independently. The assessment of risk of bias and data synthesis will be conducted with RevMan V.5.2.

Results: The results will provide a high-quality synthesis of current evidence for researchers in this subject area.

Conclusion: The conclusion of our study will provide an evidence to judge whether traditional Chinese medicine formula Xiaoqinglong decoction is an effective intervention for patients with cough caused by COVID-19.

Ethics And Dissemination: Formal ethical approval is not necessary as the data cannot be individualized. The results of this protocol will be disseminated in a peer-reviewed journal or presented at relevant conferences.

Prospero Registration Number: CRD42020202079.
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http://dx.doi.org/10.1097/MD.0000000000023261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710204PMC
November 2020

Traditional Chinese medicine for corona virus disease 2019: A protocol for systematic review.

Medicine (Baltimore) 2020 Aug;99(35):e21774

Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu.

Background: Assessing the effectiveness and safety of Traditional Chinese medicine for treating patients with corona virus disease 2019 (COVID-19) is the main purpose of this systematic review protocol.

Methods: The following electronic databases will be searched from inception to April 2020: Cochrane Central Register of Controlled Trials, PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, Traditional Chinese Medicine, Chinese Biomedical Literature Database, Wan-Fang Database, and Chinese Scientific Journal Database. All published randomized controlled trials in English or Chinese related to Traditional Chinese medicine for COVID-19 will be included. Primary outcomes are time of disappearance of main symptoms and serum cytokine levels. Secondary outcomes is Accompanying symptoms disappear rate, negative COVID-19 results rate on 2 consecutive occasions CT image improvement, average hospitalization time, occurrence rate of common type to severe form, clinical cure rate, and mortality. Two reviewers will conduct the study selection, data extraction, and assessment independently. The assessment of risk of bias and data synthesis will be conducted with Review Manager Software V.5.2.

Results: The results will provide a high-quality synthesis of current evidence for researchers in this subject area.

Conclusion: The conclusion of our study will provide evidence to judge whether traditional Chinese medicine is an effective intervention for COVID-19 patients.

Prospero Registration Number: CRD42020181006.
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http://dx.doi.org/10.1097/MD.0000000000021774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458227PMC
August 2020

Failure mechanisms of pedicle screws and cortical screws fixation under large displacement: A biomechanical and microstructural study based on a clinical case scenario.

J Mech Behav Biomed Mater 2020 04 18;104:103646. Epub 2020 Jan 18.

Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. Electronic address:

Study Design: Cadaveric biomechanical with imaging analysis.

Objective: This study aims to compare the fixation failure between pedicel screws (PS) and cortical screws (CS), thus to investigate their failure mechanisms under vertical migration.

Summary Of Background Data: Due to their minimal invasive nature, CS are gaining popularity. However, contradictions exist in the literature regarding whether CS may have superior fixation failure resistance compared to PS under vertical migration.

Methods: Human vertebral specimens were examined under Dual-energy X-ray. For each specimen, PS were inserted on the left and CS on the right with rods secured. Vertical force-displacement tests were applied to rods. MicroCT images were taken pre and post-MTS® for microstructural analysis.

Results: The average T-scores of the specimens were -4±0.25. Three phases of force-displacement behaviour featuring different PS and CS failure-resistance were discovered. For phase I, the force required to migrate PS tended to be slightly higher than CS. However, during phase II, a fixation instability occurred for PS and the CS fixation strength was superior. For phase III under large displacement, CS did not require increased force to displace, whereas PS re-stabilised and revealed improved displacement resistance. Both force analysis and microstructural analysis indicated that PS migrated along the direction of the vertical loading, whereas CS had a force component in the longitudinal axis of the screw.

Conclusions: Different failure mechanisms underlay PS and CS under large vertical displacement. PS fail with trabecular bone compaction possibly altering the initial material property surround the screw. CS fail with screw cut-out due to the force component along the screw axis.
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http://dx.doi.org/10.1016/j.jmbbm.2020.103646DOI Listing
April 2020

Physical Mechanism of Concrete Damage under Compression.

Materials (Basel) 2019 Oct 11;12(20). Epub 2019 Oct 11.

School of Civil Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, China.

Although considerable effort has been taken regarding concrete damage, the physical mechanism of concrete damage under compression remains unknown. This paper presents, for the first time, the physical reality of the damage of concrete under compression in the view of statistical and probabilistic information (SPI) at the mesoscale. To investigate the mesoscale compressive fracture, the confined force chain buckling model is proposed; using which the mesoscale parameters concerned could be directly from nanoindentation by random field theory. Then, the mesoscale parameters could also be identified from macro-testing using the stochastic damage model. In addition, the link between these two mesoscale parameters could be established by the relative entropy. A good agreement between them from nano- and macro- testing when the constraint factor approaches around 33, indicates that the mesoscale parameters in the stochastic damage model could be verified through the present research. Our results suggest that concrete damage is strongly dependent on the mesoscale random failure, where meso-randomness originates from intrinsic meso-inhomogeneity and meso-fracture arises physically from the buckling of the confined force chain system. The mesoscale random buckling of the confined force chain system above tends to constitute the physical mechanism of concrete damage under compression.
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http://dx.doi.org/10.3390/ma12203295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829316PMC
October 2019

Influence of viral infection on the relationships between airway cytokines and lung function in asthmatic children.

Respir Res 2018 Nov 21;19(1):228. Epub 2018 Nov 21.

Departments of Pediatrics and Communicable Diseases, University of Michigan Medical School, 1150 W. Medical Center Dr., Building MSRB2, Room 3570B, Ann Arbor, MI, 48109-5688, USA.

Background: Few longitudinal studies examine inflammation and lung function in asthma. We sought to determine the cytokines that reduce airflow, and the influence of respiratory viral infections on these relationships.

Methods: Children underwent home collections of nasal lavage during scheduled surveillance periods and self-reported respiratory illnesses. We studied 53 children for one year, analyzing 392 surveillance samples and 203 samples from 85 respiratory illnesses. Generalized estimated equations were used to evaluate associations between nasal lavage biomarkers (7 mRNAs, 10 proteins), lung function and viral infection.

Results: As anticipated, viral infection was associated with increased cytokines and reduced FVC and FEV. However, we found frequent and strong interactions between biomarkers and virus on lung function. For example, in the absence of viral infection, CXCL10 mRNA, MDA5 mRNA, CXCL10, IL-4, IL-13, CCL4, CCL5, CCL20 and CCL24 were negatively associated with FVC. In contrast, during infection, the opposite relationship was frequently found, with IL-4, IL-13, CCL5, CCL20 and CCL24 levels associated with less severe reductions in both FVC and FEV.

Conclusions: In asthmatic children, airflow obstruction is driven by specific pro-inflammatory cytokines. In the absence of viral infection, higher cytokine levels are associated with decreasing lung function. However, with infection, there is a reversal in this relationship, with cytokine abundance associated with reduced lung function decline. While nasal samples may not reflect lower airway responses, these data suggest that some aspects of the inflammatory response may be protective against viral infection. This study may have ramifications for the treatment of viral-induced asthma exacerbations.
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http://dx.doi.org/10.1186/s12931-018-0922-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249926PMC
November 2018

Impact of community respiratory viral infections in urban children with asthma.

Ann Allergy Asthma Immunol 2019 02 29;122(2):175-183.e2. Epub 2018 Oct 29.

Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address:

Background: Upper respiratory tract viral infections cause asthma exacerbations in children. However, the impact of natural colds on children with asthma in the community, particularly in the high-risk urban environment, is less well defined.

Objective: We hypothesized that children with high-symptom upper respiratory viral infections have reduced airway function and greater respiratory tract inflammation than children with virus-positive low-symptom illnesses or virus-negative upper respiratory tract symptoms.

Methods: We studied 53 children with asthma from Detroit, Michigan, during scheduled surveillance periods and self-reported respiratory illnesses for 1 year. Symptom score, spirometry, fraction of exhaled nitric oxide (FeNO), and nasal aspirate biomarkers, and viral nucleic acid and rhinovirus (RV) copy number were assessed.

Results: Of 658 aspirates collected, 22.9% of surveillance samples and 33.7% of respiratory illnesses were virus-positive. Compared with the virus-negative asymptomatic condition, children with severe colds (symptom score ≥5) showed reduced forced expiratory flow at 25% to 75% of the pulmonary volume (FEF), higher nasal messenger RNA expression of C-X-C motif chemokine ligand (CXCL)-10 and melanoma differentiation-associated protein 5, and higher protein abundance of CXCL8, CXCL10 and C-C motif chemokine ligands (CCL)-2, CCL4, CCL20, and CCL24. Children with mild (symptom score, 1-4) and asymptomatic infections showed normal airway function and fewer biomarker elevations. Virus-negative cold-like illnesses demonstrated increased FeNO, minimal biomarker elevation, and normal airflow. The RV copy number was associated with nasal chemokine levels but not symptom score.

Conclusion: Urban children with asthma with high-symptom respiratory viral infections have reduced FEF and more elevations of nasal biomarkers than children with mild or symptomatic infections, or virus-negative illnesses.
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http://dx.doi.org/10.1016/j.anai.2018.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360098PMC
February 2019

A novel fracture mechanics model explaining the axial penetration of bone-like porous, compressible solids by various orthopaedic implant tips.

J Mech Behav Biomed Mater 2018 04 3;80:128-136. Epub 2018 Feb 3.

Department of Mechanical Engineering, Faculty of Engineering, The University of Hong Kong, Hong Kong, China.

Many features of orthopaedic implants have been previously examined regarding their influence on migration in trabecular bone under axial loading, with screw thread design being one of the most prominent examples. There has been comparatively little investigation, however, of the influence that implant tip design has on migration under axial loads. We present a novel fracture mechanics model that explains how differences in tip design affect the force required for axial penetration of porous, compressible solids similar to trabecular bone. Three tip designs were considered based on typical 5 mm diameter orthopaedic locking screws: flat and conical tip designs, as well as a novel elastomeric tip. Ten axial penetration trials were conducted for each tip design. In order to isolate the effect of tip design on axial migration from that of the threads, smooth steel rods were used. Tip designs were inserted into polyurethane foam commonly used to represent osteoporotic trabecular bone tissue (ASTM Type 10, 0.16 g/cc) to a depth of 10 mm at a rate of 2 mm/min, while force and position were recorded. At maximum depth, elastomeric tips were found to require the greatest force for axial migration (mean of 248.24 N, 95% Confidence Interval [CI]: 238.1-258.4 N), followed by conical tips (mean of 143.46 N, 95% CI: 142.1-144.9 N), and flat tips (mean of 113.88 N, 95% CI: 112.2-115.5 N). This experiment was repeated in cross-section while recording video of material compaction through a transparent window. Strain fields for each tip design were then generated from these videos using digital image correlation (DIC) software. A novel fracture mechanics model, combining the Griffith with porous material compaction, was developed to explain the performance differences observed between the three tip designs. This model predicted that steady-state stress would be roughly the same (~ 4 MPa) across all designs, a finding consistent with the experimental results. The model also suggested that crack formation and friction are negligible mechanisms of energy absorption during axial penetration of porous compressible solids similar to trabecular bone. Material compaction appears to be the dominant mechanism of energy absorption, regardless of tip design. The cross-sectional area of the compacted material formed during migration of the implant tip during axial penetration was shown to be a strong determinant of the force required for migration to occur (Pearson Coefficient = 0.902, p < .001). As such, implant tips designed to maximize the cross-sectional area of compacted material - such as the elastomeric and conical tips in the present study - may be useful in reducing excessive implant migration under axial loads in trabecular bone.
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http://dx.doi.org/10.1016/j.jmbbm.2018.01.025DOI Listing
April 2018

Preparation of chitosan sulfate and vesicle formation with a conventional cationic surfactant.

Carbohydr Polym 2018 Mar 17;183:240-245. Epub 2017 Dec 17.

China Research Institute of Daily Chemical Industry, Taiyuan 030001, PR China.

Chitosan of high molecular weight and 85% deacetylation was used to prepare chitosan sulfate (CHS) by employing an industrial recognized green and highly reactive sulfating agent gas SO. FT-IR and solid-state CP-MAS C NMR spectra confirmed that sulfate groups were successfully introduced into chitosan chains with a sulfur content of 16.50% and the substitution degree of 1.75 according to the results of elemental analysis. The aggregation behavior of the mixture of chitosan sulfate polyelectrolyte and oppositely charged surfactant cetyltrimethylammonium bromide (CTAB) was characterized by surface tension, steady-state fluorescent, turbidity, ζ potential and transmission electron microscopy. The results indicate that the CHS/CTAB mixture has pretty high surface activity and low critical aggregation concentration. The CHS/CTAB mixture successively forms spherical aggregates, precipitation, vesicles and micelle aggregates coated by CHS chains by increasing surfactant concentration due to the cooperative hydrophobic and electrostatic interactions.
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http://dx.doi.org/10.1016/j.carbpol.2017.12.032DOI Listing
March 2018

Involvement of glucose-regulated protein 78 and spliced X-box binding protein 1 in the protective effect of gliclazide in diabetic nephropathy.

Diabetes Res Clin Pract 2018 Dec 4;146:41-47. Epub 2017 May 4.

Department of Chinese with Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.

Aims: To testing whether endoplasmic reticulum (ER) stress contributes to the development of diabetic nephropathy. Investigated the effect of gliclazide, an oral antihyperglycemic agent, in a rat model of diabetic nephropathy and the underlying mechanism related to the ER stress response.

Methods: Sixty SD rats were divided into six groups. Diabetic nephropathy was induced in 30 rats with a streptozotocin (STZ) injection and high fat diet, which were then treated with saline, gliclazide or 4-PBA. 20 rats were treated with Tunicamycin (TM) one-time intraperitoneal injection, following treated with saline or gliclazide. Blood glucose, kidney index and function were evaluated. Light and transmission electron microscopy (TEM) were used to observe kidney histological changes. Quantitative real-time PCR and western blot were performed to access the mRNA and protein levels of glucose-regulated protein 78 (GRP78) and spliced X-box binding protein 1 (sXBP1) in glomeruli.

Result: STZ-induced diabetic rats evidenced nephropathy by higher serum creatinine (sCr), blood urea nitrogen (BUN), microalbuminuria (MAU), and kidney index. Histological examination and TEM assay showed abnormal renal structures including thick glomerular basement membrane and mesangial cell expansion. The same changes were found in TM-treated rats. Gliclazide-treated had similar kidney index, but lower glucose levels, sCr, BUN, and MAU, compared with both saline and 4-PBA-treated diabetic rats or saline-treated TM rats. Synchronize with significantly lower Grp78 and sXbp1 mRNA and protein levels.

Conclusion: Diabetes-induced nephropathy is associated with ER stress. Gliclazide treatment lessens diabetic nephropathy, probably partially by suppressing the GRP78- and sXBP1-mediated ER response.
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http://dx.doi.org/10.1016/j.diabres.2017.04.019DOI Listing
December 2018

Development and initial validation of a novel smoothed-particle hydrodynamics-based simulation model of trabecular bone penetration by metallic implants.

J Orthop Res 2018 04 16;36(4):1114-1123. Epub 2017 Nov 16.

LKS Faculty of Medicine, Department of Orthopaedics & Traumatology, The University of Hong Kong, China.

A novel computational model of implant migration in trabecular bone was developed using smoothed-particle hydrodynamics (SPH), and an initial validation was performed via correlation with experimental data. Six fresh-frozen human cadaveric specimens measuring 10 × 10 × 20 mm were extracted from the proximal femurs of female donors (mean age of 82 years, range 75-90, BV/TV ratios between 17.88% and 30.49%). These specimens were then penetrated under axial loading to a depth of 10 mm with 5 mm diameter cylindrical indenters bearing either flat or sharp/conical tip designs similar to blunt and self-tapping cancellous screws, assigned in a random manner. SPH models were constructed based on microCT scans (17.33 µm) of the cadaveric specimens. Two initial specimens were used for calibration of material model parameters. The remaining four specimens were then simulated in silico using identical material model parameters. Peak forces varied between 92.0 and 365.0 N in the experiments, and 115.5-352.2 N in the SPH simulations. The concordance correlation coefficient between experimental and simulated pairs was 0.888, with a 95%CI of 0.8832-0.8926, a Pearson ρ (precision) value of 0.9396, and a bias correction factor Cb (accuracy) value of 0.945. Patterns of bone compaction were qualitatively similar; both experimental and simulated flat-tipped indenters produced dense regions of compacted material adjacent to the advancing face of the indenter, while sharp-tipped indenters deposited compacted material along their peripheries. Simulations based on SPH can produce accurate predictions of trabecular bone penetration that are useful for characterizing implant performance under high-strain loading conditions. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1114-1123, 2018.
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http://dx.doi.org/10.1002/jor.23734DOI Listing
April 2018

Valproic Acid Combined With Postcardiac Arrest Hypothermic-Targeted Temperature Management Prevents Delayed Seizures and Improves Survival in a Rat Cardiac Arrest Model.

Crit Care Med 2017 Nov;45(11):e1149-e1156

1Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 2Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI. 3Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, MI. 4Department of Neurology, University of Michigan Medical School, Ann Arbor, MI.

Objectives: High-dose valproic acid in combination with hypothermic-targeted temperature management has been reported to synergistically improve neurologic outcomes after cardiac arrest. This study investigated the potential synergistic mechanisms.

Design: Prospective, randomized, experimental study.

Setting: University research institution.

Subjects: Male Long Evans rats.

Intervention: Rats resuscitated from asphyxial cardiac arrest were randomized to one of the three groups: normothermic-targeted temperature management (37°C ± 1°C), hypothermic-targeted temperature management (33° ± 1° × 24 hr + placebo infusion), hypothermic-targeted temperature management plus high-dose valproic acid (300 mg/kg IV × 1 initiated 5 min post return of spontaneous circulation and infused over 20 min) (hypothermic-targeted temperature management + valproic acid).

Measurements And Main Results: Seventy-two-hour survival was significantly greater with hypothermic-targeted temperature management + valproic acid, compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p < 0.05). Survival with good neurologic function, neurodegeneration, expression of HSP70, phosphorylation of Akt and Erk1/2 were not significantly different between hypothermic-targeted temperature management and hypothermic-targeted temperature management + valproic acid. The prevalence of seizures during the first 72-hour postcardiac arrest was significantly lower with hypothermic-targeted temperature management + valproic acid compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p = 0.01).

Conclusions: High-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000002690DOI Listing
November 2017

Combined intra- and post-cardiac arrest hypothermic-targeted temperature management in a rat model of asphyxial cardiac arrest improves survival and neurologic outcome compared to either strategy alone.

Resuscitation 2016 10 10;107:94-101. Epub 2016 Aug 10.

Department of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States; Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, United States; Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, MI, United States. Electronic address:

Aim: Post-cardiac arrest hypothermic-targeted temperature management (HTTM) improves outcomes in preclinical cardiac arrest studies. However, inadequate understanding of the mechanisms and therapeutic windows remains a barrier to optimization. We tested the hypothesis that combined intra- and post-cardiac arrest HTTM provides a synergistic outcome benefit compared to either strategy alone.

Methods: Rats subjected to 8-min asphyxial cardiac arrest were block randomized to 4 treatment groups (n=12/group): NTTM) normothermic-targeted temperature management; 1-24 HTTM) HTTM initiated 1h post-ROSC and maintained for 24h; Intra-1 HTTM) HTTM initiated at CPR onset and maintained for 1h; and Intra-24 HTTM) HTTM initiated at CPR onset and maintained for 24h. HTTM was induced by nasopharyngeal cooling and maintained using an automated temperature regulation system. Target temperature range was 36.5-37.5°C for NTTM and 32.0-34.0°C for HTTM. Post-arrest neurologic function score (NFS) was measured daily, and rats surviving 72h were euthanized for histological analysis of neurodegeneration.

Results: Target brain temperature was achieved 7.8±3.3min after initiating intra-arrest cooling. The survival rate was 42%, 50%, 50%, and 92% in the NTTM, 1-24 HTTM, Intra-1 HTTM, and Intra-24 HTTM groups, respectively (p<0.05, Intra-24 group vs. all other groups). The rate of survival with good neurologic function (NFS≥450) was 33% in the Intra-24 HTTM group vs. 0% in all other groups (mid p<0.05). Hippocampal CA1 sector neurodegeneration was significantly reduced in the Intra-24 HTTM group compared to all other groups (p<0.05).

Conclusion: Combined intra- and post-cardiac arrest HTTM has greater outcome benefits than either strategy alone.
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http://dx.doi.org/10.1016/j.resuscitation.2016.07.232DOI Listing
October 2016

CRISPR-based genome editing and expression control systems in Clostridium acetobutylicum and Clostridium beijerinckii.

Biotechnol J 2016 Jul 13;11(7):961-72. Epub 2016 Jun 13.

Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Solventogenic clostridia are important industrial microorganisms that produce various chemicals and fuels. Effective genetic tools would facilitate physiological studies aimed both at improving our understanding of metabolism and optimizing solvent productivity through metabolic engineering. Here we have developed an all-in-one, CRISPR-based genome editing plasmid, pNICKclos, that can be used to achieve successive rounds of gene editing in Clostridium acetobutylicum ATCC 824 and Clostridium beijerinckii NCIMB 8052 with efficiencies varying from 6.7% to 100% and 18.8% to 100%, respectively. The plasmid specifies the requisite target-specific guide RNA, the gene encoding the Streptococcus pyogenes Cas9 nickase and the genome editing template encompassing the gene-specific homology arms. It can be used to create single target mutants within three days, with a further two days required for the curing of the pNICKclos plasmid ready for a second round of mutagenesis. A S. pyogenes dCas9-mediated gene regulation control system, pdCASclos, was also developed and used in a CRISPRi strategy to successfully repress the expression of spo0A in C. acetobutylicum and C. beijerinckii. The combined application of the established high efficiency CRISPR-Cas9 based genome editing and regulation control systems will greatly accelerate future progress in the understanding and manipulation of metabolism in solventogenic clostridia.
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http://dx.doi.org/10.1002/biot.201600053DOI Listing
July 2016

[New methods for cloning large gene clusters based on CRISPR/cas9].

Sheng Wu Gong Cheng Xue Bao 2016 Apr;32(4):401-408

CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200032, China.

Cloning of large genomic sequences is an enabling technology in synthetic biology. To obtain large gene fragments, traditional cloning methods are faced with various defects, for instance, random library cloning relies always on high-throughput screening. It is difficult to get gene fragments more than 10 kb by PCR amplification. Assembly of small fragments is labor intensive with high mutation rates. It is difficult to find suitable cleavage sites on the fragment ends by restriction endonuclease. Recently genome-wide editing creates a new high-performance large fragments cloning methods. For example, CRISPR/cas9 system can identify and cut 20 bp nucleic acid sequences recognition sites used to obtain any desired gene fragments; if combined with Gibson or transformation associated recombination (TAR) assembly technology, these methods can efficiently clone large fragments. This article introduces large fragments cloning technology by classification, then proposes the choice criteria of methods for cloning gene fragments of different sizes.
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http://dx.doi.org/10.13345/j.cjb.150491DOI Listing
April 2016

Thrombolytic-Enhanced Extracorporeal Cardiopulmonary Resuscitation After Prolonged Cardiac Arrest.

Crit Care Med 2016 Feb;44(2):e58-69

1Extracorporeal Life Support Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI. 2Department of Anesthesia, Critical Care, and Pain Medicine, University of Milano, Milano, Italy. 3Department of Emergency Medicine, University of Michigan, Ann Arbor, MI. 4Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, MI. 5Department of Pediatric Cardiology, University of Michigan, Ann Arbor, MI. 6Department of Neurology, University of Michigan, Ann Arbor, MI. 7Department of Neurosurgery, University of Michigan, Ann Arbor, MI. 8Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI. 9Department of Surgery, Section of Transplantation, University of Michigan, Ann Arbor, MI.

Objective: To investigate the effects of the combination of extracorporeal cardiopulmonary resuscitation and thrombolytic therapy on the recovery of vital organ function after prolonged cardiac arrest.

Design: Laboratory investigation.

Setting: University laboratory.

Subjects: Pigs.

Interventions: Animals underwent 30-minute untreated ventricular fibrillation cardiac arrest followed by extracorporeal cardiopulmonary resuscitation for 6 hours. Animals were allocated into two experimental groups: t-extracorporeal cardiopulmonary resuscitation (t-ECPR) group, which received streptokinase 1 million units, and control extracorporeal cardiopulmonary resuscitation (c-ECPR), which did not receive streptokinase. In both groups, the resuscitation protocol included the following physiologic targets: mean arterial pressure greater than 70 mm Hg, cerebral perfusion pressure greater than 50 mm Hg, PaO2 150 ± 50 torr (20 ± 7 kPa), PaCO2 40 ± 5 torr (5 ± 1 kPa), and core temperature 33°C ± 1°C. Defibrillation was attempted after 30 minutes of extracorporeal cardiopulmonary resuscitation.

Measurements And Main Results: A cardiac resuscitability score was assessed on the basis of success of defibrillation, return of spontaneous heart beat, weanability from extracorporeal cardiopulmonary resuscitation, and left ventricular systolic function after weaning. The addition of thrombolytic to extracorporeal cardiopulmonary resuscitation significantly improved cardiac resuscitability (3.7 ± 1.6 in t-ECPR vs 1.0 ± 1.5 in c-ECPR). Arterial lactate clearance was higher in t-ECPR than in c-ECPR (40% ± 15% vs 18% ± 21%). At the end of the experiment, the intracranial pressure was significantly higher in c-ECPR than in t-ECPR. Recovery of brain electrical activity, as assessed by quantitative analysis of electroencephalogram signal, and ischemic neuronal injury on histopathologic examination did not differ between groups. Animals in t-ECPR group did not have increased bleeding complications, including intracerebral hemorrhages.

Conclusions: In a porcine model of prolonged cardiac arrest, t-ECPR improved cardiac resuscitability and reduced brain edema, without increasing bleeding complications. However, early electroencephalogram recovery and ischemic neuronal injury were not improved.
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http://dx.doi.org/10.1097/CCM.0000000000001305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948940PMC
February 2016

Dynamic Initiation and Propagation of Multiple Cracks in Brittle Materials.

Materials (Basel) 2013 Jul 31;6(8):3241-3253. Epub 2013 Jul 31.

Department of Building Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, China.

Brittle materials such as rock and ceramic usually exhibit apparent increases of strength and toughness when subjected to dynamic loading. The reasons for this phenomenon are not yet well understood, although a number of hypotheses have been proposed. Based on dynamic fracture mechanics, the present work offers an alternate insight into the dynamic behaviors of brittle materials. Firstly, a single crack subjected to stress wave excitations is investigated to obtain the dynamic crack-tip stress field and the dynamic stress intensity factor. Second, based on the analysis of dynamic stress intensity factor, the fracture initiation sizes and crack size distribution under different loading rates are obtained, and the power law with the exponent of -2/3 is derived to describe the fracture initiation size. Third, with the help of the energy balance concept, the dynamic increase of material strength is directly derived based on the proposed multiple crack evolving criterion. Finally, the model prediction is compared with the dynamic impact experiments, and the model results agree well with the experimentally measured dynamic increasing factor (DIF).
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http://dx.doi.org/10.3390/ma6083241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521245PMC
July 2013

Dynamic fracture in irregularly structured systems.

Authors:
Xiaodan Ren Jie Li

Phys Rev E Stat Nonlin Soft Matter Phys 2012 May 7;85(5 Pt 2):055102. Epub 2012 May 7.

School of Civil Engineering, Tongji University, Shanghai, China.

Although commonly used materials are composed of irregular microstructures, most existing numerical methods for fracture dynamics are developed via regular discretizations. In the present Rapid Communication we investigate the dynamic fracture numerically by irregular domain discretizations. To explore the relationship between microscopic crack branching and the macroscopic instability of fracture dynamics, we simulate detailed diagrams for the crack branching and also calculate the crack speeds by varying the parameters of crack-tip cohesion. In particular, an equation to describe the relation between the crack speed and the fracture energy is proposed based on the simulation results. The present results indicate that the irregularities of mesoscopic structure contribute to the intrinsic instabilities of dynamic fracture and eventually to the crack speed. And the single-crack continuum theory should be at least carefully modified to describe the dynamic fracture governed by the complex branching and fluctuations.
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http://dx.doi.org/10.1103/PhysRevE.85.055102DOI Listing
May 2012

IL-22 is involved in liver regeneration after hepatectomy.

Am J Physiol Gastrointest Liver Physiol 2010 Jan 29;298(1):G74-80. Epub 2009 Oct 29.

Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Hepatocyte proliferation following partial hepatectomy is an important component of liver regeneration, and recent in vitro studies have shown that IL-22 is involved in cellular proliferation in a variety of cell types, including hepatocytes. IL-22 functions through IL-10Rbeta and IL-22Ralpha. The goal of this study was to investigate the potential role of IL-22 in liver regeneration after 70% hepatectomy. Following 70% hepatectomy, done under general anesthesia in mice, serum IL-22 and hepatic IL-22Ralpha mRNA were significantly increased. Although administration of exogenous IL-22 prior to hepatectomy did not increase hepatocyte proliferation, administration of anti-IL-22 antibody before hepatectomy did significantly decrease hepatocyte proliferation. Furthermore, IL-22 treatment prior to 70% hepatectomy induced stat-3 activation; no significant changes were seen in ERK1/2 activation, stat-1 activation, or stat-5 activation. IL-22 pretreatment also significantly increased hepatic and serum IL-6 levels. In addition, animals treated with anti-IL-22 antibody also expressed less TGF-alpha. In conclusion, these data suggest that IL-22 is involved in liver regeneration and this may be due to interaction with IL-6 and TGF-alpha cascades.
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http://dx.doi.org/10.1152/ajpgi.00075.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806105PMC
January 2010

Stem cell factor and its receptor, c-kit, are important for hepatocyte proliferation in wild-type and tumor necrosis factor receptor-1 knockout mice after 70% hepatectomy.

Surgery 2008 Jun;143(6):790-802

Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich.

Background: Stem cell factor (SCF) has well-known proliferative effects on hematopoietic cells. SCF also has effects on differentiation and proliferation in other cell types. Interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha have proliferative effects in the liver. Recent studies in our laboratory have linked SCF's hepatoproliferative actions to those of IL-6, demonstrating that IL-6-induced hepatocyte proliferation depends, at least in part, on SCF. We now hypothesize that TNF-alpha's hepatoproliferative effects are also dependent on SCF.

Methods And Results: In vitro studies using primary mouse hepatocytes show that SCF is induced by TNF-alpha; anti-SCF antibody treatment in this system inhibits TNF-alpha-induced hepatocyte proliferation, suggesting that TNF-alpha-induced hepatocyte proliferation is also SCF dependent. Additional in vivo experiments were performed in which wild type and/or TNF-alpha receptor-1 knockout mice (TNFR1(-/-)) were subjected to 70% hepatectomy or sham laparotomy. TNFR1(-/-) mice are known to have delayed hepatic regeneration after partial hepatectomy. Initial experiments demonstrated that the SCF receptor, c-kit, is upregulated after partial hepatectomy in wild-type mice, further emphasizing the importance of this system in the restoration of hepatic mass. SCF administration to TNFR1(-/-) mice in the context of partial hepatectomy restores hepatocyte proliferation to normal. Further, SCF administration to TNFR1(-/-) mice before hepatectomy increases phosphotyrosine signal transducer and activator (p-stat-3) levels, suggesting that SCF-induced increases in hepatocyte proliferation may also be stat-3 mediated.

Conclusions: These data suggest that TNF-alpha-induced hepatocyte proliferation depends, at least in part, on SCF and that SCF and its receptor, c-kit, are important for the liver's regenerative processes.
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http://dx.doi.org/10.1016/j.surg.2008.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495772PMC
June 2008

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice.

Hepatology 2006 Sep;44(3):540-9

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0331, USA.

Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown an increase in the levels of matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) after partial hepatectomy. The goal of this study was to investigate the role of MMP-9 in liver regeneration after partial hepatectomy. A 70% hepatectomy or sham laparotomy was performed in wild-type or MMP-9-deficient (MMP-9-/-) mice. Hepatic regeneration was determined by liver weight/total body weight ratios and BrdU staining, which was used to a calculate mitotic index at several times postoperatively. Cytokine and growth factor expression was evaluated by Luminex bead-based ELISA and Western blots. Finally, the effect of MMP-9 on apoptosis was measured using TUNEL and caspase expression. The MMP-9-/- animals had a delayed hepatic regenerative response when compared with wild-type controls. The MMP-9-deficient animals expressed significantly less VEGF, HGF, and TNF-alpha between days 2 and 3 post-hepatectomy. Apoptosis, as measured by TUNEL staining and caspase expression, was decreased in the MMP-9-/-. In conclusion, MMP-9 plays an important role in liver regeneration after partial hepatectomy by affecting matrix remodeling, as well as cytokine, growth factor, and caspase expression.
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http://dx.doi.org/10.1002/hep.21314DOI Listing
September 2006

Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy.

J Clin Invest 2003 Nov;112(9):1407-18

Department of Surgery, University of Michigan, Medical School, Ann Arbor, Michigan 48109-0331, USA.

Stem cell factor (SCF) is a molecule with known proliferative effects on hematopoietic cells. More recent studies suggest that this molecule may also have effects on cellular differentiation and proliferation in other types of cells. The current investigations demonstrate that there is a large reservoir of SCF in the liver, that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits hepatocyte proliferation after partial hepatectomy; if SCF is replaced in the genetically SCF-deficient mice after partial hepatectomy, hepatocyte proliferation is restored to that seen in WT animals. Furthermore, SCF administration to IL-6 knockout mice also restores hepatocyte proliferation to normal. In vitro studies using primary mouse hepatocytes demonstrate that SCF causes hepatocyte proliferation and is induced by IL-6 and that treatment with anti-SCF antibodies inhibits IL-6-induced hepatocyte proliferation. Further in vivo studies in IL-6 knockout mice demonstrate that SCF administration to these animals increases p-stat3 levels, suggesting that the SCF-induced increase in hepatocyte proliferation in this system is stat3-mediated.
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http://dx.doi.org/10.1172/JCI17391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC228393PMC
November 2003

Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse.

Am J Pathol 2003 Aug;163(2):563-70

Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Recent studies show CXC chemokine elevations after hepatic resection; blockade of epithelial neutrophil-activating protein (ENA-78), a CXC chemokine, retards hepatic regeneration after resection. Additional studies demonstrate that exogenous macrophage inflammatory protein (MIP)-2, another CXC chemokine, is therapeutic in a murine acetaminophen toxicity model when other therapies fail. The current investigations study MIP-2's effects on the cellular mechanisms involved in liver regeneration in mice after 70% hepatectomy. Administration of exogenous MIP-2 after 70% hepatectomy dramatically increased hepatocyte proliferation as measured by 5-bromo-2'-deoxyuridine staining. Signal transducer and activator of transcription-3 (stat-3) was also detected in greater abundance and persisted in hepatic nuclear extracts from MIP-2-treated mice compared with control mice after hepatic resection. Further, inhibition of the MIP-2 receptor, CXCR2, decreased baseline hepatocyte proliferation and stat-3 expression in the setting of partial hepatectomy. These data show that MIP-2 is important for hepatocyte proliferation after partial hepatectomy and that pharmacological MIP-2 doses after hepatic injury accelerate hepatic regeneration.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868215PMC
http://dx.doi.org/10.1016/S0002-9440(10)63684-XDOI Listing
August 2003

CXC chemokine expression after stimulation with interferon-gamma in primary rat hepatocytes in culture.

Shock 2002 Jun;17(6):513-20

Department of Surgery, University of Michigan Medical School, Ann Arbor 48109, USA.

Monokine-induced by gamma interferon (MIG) and gamma-interferon-inducible protein (IP-10) are members of the CXC chemokine family that have been shown to be induced by interferon-gamma (IFNy) in some cell types. The purpose of this investigation was to determine whether IFNgamma influences CXC chemokine production, particularly MIG and IP-10, in primary rat hepatocytes in culture. Previous experiments in our laboratory have demonstrated that pharmacologic doses of IFNgamma in an in vivo model of hepatic ischemia/reperfusion-induced liver injury resulted in increased hepatic levels of IP-10 and MIG and decreased hepatic levels of macrophage inflammatory protein-2, Kupffer cells, and epithelial neutrophil-activating protein, with a concomitant decrease in neutrophil-mediated hepatic injury. In the current investigation, MIG and IP-10 mRNA and protein were up-regulated in primary rat hepatocytes in vitro in response to IFNgamma. Although MIG and IP-10 mRNA were both somewhat increased at early time points, larger increases in these chemokines were seen at later time points, specifically at 24, 48, and 72 h of incubation as compared to controls. Levels of Kupffer cells and macrophage inflammatory protein-2 mRNA after IFNgamma were negligible and similar to those seen in controls. These findings were confirmed by enzyme-linked immunosorbent assay analysis. These studies demonstrate that IFNgamma in vitro up-regulates the production of MIG and IP-10, at both the mRNA and protein levels.
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http://dx.doi.org/10.1097/00024382-200206000-00013DOI Listing
June 2002
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