Long non-coding RNA H19 regulates neurogenesis of induced neural stem cells in a mouse model of closed head injury

Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.

Induced neural stem cells regulate microglial activation through Akt-mediated upregulation of CXCR4 and Crry in a mouse model of closed head injury

Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.

Changes of Nitric Oxide and Its Relationship with Clinical Features,Intracranial Pressure and Outcome in Acute Head Injury

To investigate the content and dynamics of nitric oxide (NO) in the cerebrospinal fluid (CSF) of patients with acute head injury and to clarify the relationship of NO with clinical features and intracranial pressure (ICP) as well as outcomes, 38 adults with acute head injury were studied. Glasgow Coma Scale (GCS) obtained at admission and Glasgow Outcome Scale (GOS) 3 months after injury was assessed. ICP was surveyed via intraventricular catheter and lumbar puncture and CSF samples were obtained simultaneously. NO was determined with Griess reagents. Results showed that NO peak content in the head injury group was significantly higher than that of the control group. During dynamic research, no peak content of mildly injured cases and severely injured ones appeared in different time windows respectively. The peak value of NO was distinctly higher in the severe group than in the mild group. NO peak value of the raised ICP group was remarkably higher than that of the normal ICP group. The peak value of NO was considerately higher in the poor outcome group than in the good outcome group. When the content of NO was over 6. 5 μmol/L, the rate of poor outcome was increased. There existed a correlation between NO and GCS, ICP and GOS. It is concluded that the content of NO was increased in patients with acute head injury and the changes of NO had different time windows in severely injured patients and mildly injured ones. The more sever the injury, the higher the NO content; and the more serious the secondary brain injury and brain edema, the worse the outcomes. When NO is combined with GCS, GOS and ICP, it increases the accuracy of judgement to the degree of head injury and outcome.

Early enteral nutrition supplemented with probiotics improved the clinical outcomesin patients with severe head injury： protocol for a meta-analysis of randomizedcontrolled trials

Objective： The aim of this systematic review of randomized controlled trials （RCTs） is to determine the effects of earlyenteral nutrition supplemented with probiotics on clinical outcomes in patients with SHI.Methods and analysis： A systematic search will be carried out in PubMed, Cochrane Central Register of ControlledTrials （CENTRAL）, China National Knowledge Infrastructure （CNKI）, WanFang database, and Chinese BiomedicalLiterature （CBM） in order to identify the randomized controlled trials （RCTs） investigated the potential of early enteralnutrition supplemented with probiotics on patients with severe head injury, as well as we will also manually check thebibliographies of eligible studies and topic-related reviews. We will assign two investigators to independently search allpotential citations, extracted data, and appraised risk of bias accordingly, and then STATA software version 12.0 will beused to statistically analyze all data.Ethics and dissemination： The ethics approval and patient written informed consent will not be required because allanalyses in the present study will be performed based on data from published studies. We will submit our systematicreview to a peer-reviewed scientific journal for publication.

An experimental and clinical study on TXA_2 and PGI_2 content after head injury

The correlation of secondary brain injury with thromboxane A_2(TXA_2) and prostacy- clin (PGI_2) levels following head injury was studied in rats and patients.Thromboxane B_2 (TXB_2) and 6-keto-PGF_(1α) in rat brain homogenate and TXB_2 in cerebral spinal fluid (CSF) of patients with severe head injury were determined by RIA.The effects of ligustrazini hydrochlo- rioi were also tested.The results showed that the concentration of TXB_2 and 6-keto-PGF_(1α) in rat brain was progressively increased within 3h after injury (P<0.01),and the ratio between TXB_2 and 6-keto-PGF_(1α)(T/K value) increased during the early stage after injury,along with the tissue damage aggravation.After the use of ligustrazini hydrochlorioi,TXB_2 content in brain decreased sharply accompanied with a drop in T/K value.Moreover,TXB_2 content in CSF increased within 7 d after injury (P<0.01),and it reached its peak value on the 3rd day. This could indicate that the metabolic imbalance between TXA_2 and PGI_2 might be one of the important factors in the development of secondary brain injury,and ligustrazini hydrochlorioi proved to have a protective effect on the brain tissue by normalizing the metabolism of TXA_2 and PGI_2.In addition,the metabolic disorders of TXA_2 in the brain tissue of head injured pa- tients have much to do with the outcome of the patients.

Risk factors of posttraumatic cerebral infarction in patients with severe and extremely severe head injury

Objective To explore pathogenesis and risk factors for posttraumatic cerebral infarction (PTCI) in patients with severe and extremely severe head injuries for the purpose of providing clues for reducing occurrence of PTCI and case-fatality. Methods Gender,age,Glasgow coma scale (GCS) ,the presence or absence of basicranial fracture,cerebral hernia or infection,surgical modality,hypotension,and the use of diuretics

Knowledge, Attitude, and Practice of Using Helmets in Children amongst Parents to Prevent Head Injuries: A Cross-Sectional Study in Riyadh, Saudi Arabia

Objectives: The primary objective was to characterize the range of Knowledge, Attitude, and Practice (KAP) of Helmet use in children amongst parents to prevent head injuries and death. Methods: This is a cross-sectional study, done by online survey using a snowball sampling technique, the number of included responses were 386 parents (Male and female) living in Riyadh Aged 21 - 60 years old or above. Results: The study showed that there is a difference in Parents’ belief in the importance of helmet use while riding a Bicycle vs Motorcycle/Quad bike and that was affected by parents’ education level, almost all the people who answered the survey (76.7%) agree that it is important for their children to wear a helmet when riding both a Bicycle and a Motorcycle or Quadbike with a cumulative percentage of (93.8%). And almost all agreed on multiple approaches to help increase helmet use be it by forcing rental shops to give out helmets, forcing sellers to recommend the use of helmets, increasing awareness campaigns, and imposing fines for not wearing helmets. Conclusions: This study is the first to explore Family helmet use while riding Bicycles and Motorcycles/Quad bikes. Although Parent’s belief in the importance of helmet use for their children was high, it is clear that the level of practice is low. With that the risk of head injuries might be high, our findings suggest that safety interventions for increasing pediatric helmet use are needed to increase helmet use and reduce the risk of head injury and hospitalization.

dl-3-n-butylphthalide reduces brain damage in mice with closed head injury

To investigate the protective effect of dl 3 n butylphthalide (NBP) as an anti cerebral ischemic drug on brain damage 24?h after closed head injury in mice Methods Closed head injury was induced by dropping a 50 g weight from a height of 18?cm on a metal impounder resting on the parietal bone in mice Results The neurotraumatic model induced impair^ment of memory function, significant cerebral edema, and disruption of the blood brain barrier dl 3 n butylphthalide (50?mg·kg 1 ) given intraperitoneally 5 minutes and 60 minutes after the onset of closed head injury was found to attenuate the impairment of memory function ( P <0 05), alleviate brain edema in the injured cerebral cortex ( P <0 05), and reduce extravasation of plasma protein bound to Evans blue dye by 63 5% ( P <0 01) NBP was also shown to increase the activity of choline acetyltransferase in the injured cortex to 0 83±0 21?ng·min 1 ·mg 1 ( P <0 01, compared with 0 48±0 14?ng·min 1 ·mg 1 of vehicle group) Conclusion NBP provides therapeutic response in experimental closed head injury

Rational design of secondary operation for penetrating head injury:A case report

Penetrating head injury is rare,and thus management of such injuries is non-standard.Early diagnosis and intraoperative comprehensive exploration are necessary considering the complexity and severity of the trauma.However,because of the lack of microsurgical techniques in local hospitals,the possible retained foreign bodies and other postoperative complications such as cerebrospinal fluid(CSF)leak usually require a rational design for a secondary operation to deal with.We present a case of a 15-year-old boy who was stabbed with a bamboo stick in his left eye.The chopsticks passed through the orbit roof and penetrated the skull base.In subsequent days,the patient sustained CSF leak and intracranial infection after an unsatisfied primary treatment in the local hospital and had to request a secondary operation in our department.Computed tomography including plain scan,three dimension recon-struction and computed tomographic angiography are used to determine the course and extent of head injury.A frontal craniotomy was performed.Three pieces of stick were found residual and removed with the comminuted orbit bone fragments.A pedicled temporalis muscle fascia graft was applied to repair the frontier skull base and a free temporalis muscle flap to seal the frontal sinus defect.Aggressive broad-spectrum antibiotics of vancomycin and meropenem were administrated for persistent fever after operation.CSF external drainage system continued for 12 days,and was removed 10 days after tem-perature returned to normal.The Glasgow coma scale score was improved to 15 at postoperative day 7 and the patient was discharged at day 22 uneventfully.We believe that appropriate preoperative surgical plan and thorough surgical exploration by microsurgery is essential for attaining a favorable outcome,especially in secondary operation.Good postoperative recovery depends on successfully management before and after operation for possible complications as well.

Chronic subdural haematoma during the COVID-19 lockdown period:late presentation with a longer interval from the initial head injury to the final presentation and diagnosis

Background:The COVID-19 novel coronavirus is contagious,and the mortality is higher in the elderly population.Lockdown in different parts of the world has been imposed since January 2020.Chronic subdural haematoma (cSDH) has a unique natural history in which symptoms can be non-specific,and the onset is insidious.This study aims to evaluate the impact of the COVID-19 pandemic on the presentation of cSDH.Methods:Consecutive adult cSDH patients admitted from 1 March 2020 to 30 April 2020 were reviewed.Exclusion criteria including those who had no definite history of head injury or the diagnosis of cSDH were made from a scheduled follow-up scan.Corresponding data during the same period in 2019 were reviewed for comparison.The primary outcome was the interval between the initial head injury and the final radiological diagnosis of cSDH.Secondary outcomes include Markwalder chronic subdural haematoma grade upon admission,length of stay in the acute hospital,and the modified Rankin scale (mRS) upon discharge.Results:For the primary outcome,the average interval between head injury and the diagnosis of cSDH was significantly longer at 56.6 days (49 to 74 days,SD 9.83 days) during the period from March to April 2020,versus 29.4 days (17 to 42 days,SD 8.59 days) in 2019 for the corresponding period (p = 0.00703).There was no significant difference in the functional outcome upon discharge.Conclusions:cSDH patients can present late during the COVID-19 lockdown period.The functional outcome was comparable when operations for drainage were timely performed.

Clinical studies on diffuse axonal injury in patients with severe closed head injury

OBJECTIVE: To discuss the clinical criteria for diagnosing diffuse axonal injury (DAI). METHODS: Clinical and computed tomographic features of 117 patients with severe closed head injury were analyzed. The authors preliminarily put forward CT diagnostic criteria of DAI, that is, 1) single or multiple small intraparenchymal hemorrhages in the cerebral hemispheres (

Effects of nimodipine on changes of endothelin after head injury in rabbits

Objective: To investigate the effects of nimodipine on changes of endothelin after head injury. Methods: Sixty five adult rabbits were randomized into an injury group (IG, n=30), a nimodipine treatment group (NTG, n=30) and a control group (CG, n=5). With their heads unfixed, the animals in IG and NTG were injured in the frontal parietal zone with BIM II bioimpact. Blood samples and brain tissue were collected before and after injury. The endothelin level was measured with RIA. Results: The endothelin level in plasma and brain tissue was significantly increased 24 hours after injury. At the 8th or/and 24th hours postinjury, the endothelin level was significantly lower in NTG than that in IG. Conclusions: Nimodipine can prevent endothelin from elevation and act as a practical endothelin antagonist after head injury clinically.

Effect of mild hypothermia on partial pressure of oxygen in brain tissue and brain temperature in patients with severe head injury

Objective: To study the changes of partial pressure of oxygen in brain tissue ( P btO 2) and brain temperature (BT) in patients in acute phase of severe head injury, and to study the effect of mild hypothermia on P btO 2 and BT. Methods: The P btO 2 and the BT of 18 patients with severe head injury were monitored, and the patients were treated with mild hypothermia within 20 hours after injury. The rectal temperature (RT) of the patients was kept on 31.5- 34.9℃ for 1-7 days ( 57.7 hours± 28.4 hours averagely), simultaneously, the indexes of P btO 2 and BT were monitored for 1-5 days (with an average of 54.8 hours± 27.0 hours). According to Glasgow Outcome Scale (GOS), the prognosis of the patients was evaluated at 6 months after injury. Results: Within 24 hours after severe head injury, the P btO 2 was significantly lower ( 9.6 mm Hg± 6.8 mm Hg, 1 mm Hg= 0.133 kPa) than the normal value (16-40 mm Hg). After treatment of mild hypothermia, the mean P btO 2 increased to 28.7 mm Hg± 8.8 mm Hg during the first 24 hours, and the P btO 2 was still maintained within the range of normal value at 3 days after injury. The BT was higher than the RT in the patients in acute phase of severe head injury, and the difference between the BT and the RT significantly increased after treatment of mild hypothermia. Hyperventilation (the partial pressure of carbon dioxide in artery (P aCO 2)≈25 mm Hg) decreased the high intracranial pressure (ICP) and significantly decreased the P btO 2. Conclusions: This study demonstrates that P ptO 2 and BT monitoring is a safe, reliable and sensitive diagnostic method to follow cerebral oxygenation. It might become an important tool in our treatment regime for patients in the acute phase of severe head injury requiring hypothermia and hyperventilation.

Moderate hypothermia therapy for patients with severe head injury

Objective: To evaluate the effect and safety of early moderate hypothermia therapy (MHT) on patients with head injury by using parallel control test. Methods: Thirty patients with severe head injury within 6 hours after accidents were treated by MHT generally for 4 10 days. The other 30 patients with similar head injury treated routinely were enrolled for a parallel control test. The mortality, morbidity and changes of some neuro functional indexes as Glasgow Coma Scores, and Glasgow Outcome Scale, levels of endothelin and some other factors of neurobiochemistry in blood plasma were observed. Meanwhile, the dynamic monitoring by transcranial Doppler ultrasonography was conducted in these patients. Results: The mortality in MHT group was significantly lower than that in control group. MHT not only reduced endothelin but also increased the brain biochemical factors, which were helpful to the protection of neurons in the early brain ischemia after head injury. Conclusions: Early MHT can help reduce mortality and morbidity in patients with acute head injury.

The influence of traumatic subarachnoid hemorrhage on prognosis of head injury

Objective: To study the influence of traumatic subarachnoid hemorrhage on secondary intracranial damage in GCS 13 15 head injuries and prognosis. Methods: One hundred and twenty eight patients with mild head injury, including 64 with subarachnoid hemorrhage and 64 without subarachnoid hemorrhage, were selected and analyzed according to the changes of their conditions after injury. Results: Intracranial abnormality was found in 14 patients ( 21.87 %) with subarachnoid hemorrhage and only in 4 patients ( 6.25 %) without subarachnoid hemorrhage (P< 0.01 ). In the 14 patients, 4 were given surgical treatment. Mild disability was in 2 patients and 2 completely recovered. The rest were conservatively treated and achieved complete recovery at last. Conclusions: Traumatic subarachnoid hemorrhage, as a factor of intracranial complications in mild head injury should be given much attention. Early drainage of bloody cerebrospinal fluid by lumbar puncture is an effective method for prevention and treatment of complications in mild head injury.

Prospective survey on neurosurgical intensive care for patients with severe head injury

Objective:: To prospectively compare the clinical outcome of intensive care therapy (ICT) with that of conventional care therapy (CCT) in severe head injured patients. Methods: Patients with severe head injury were assigned randomly into Group ICT and Group CCT, 100 patients in each group. Patients in Group ICT accepted intensive care therapy in neurosurgical intensive care (NIC) unit for the first 2 weeks after admission, while patients in Group CCT accepted conventional care therapy in ordinary ward. The outcomes were evaluated 3 months after injury. Results: There was a significant increase in good recovery (54%) (χ 2= 4.43 , P< 0.05 ) and significant decrease of death (25%) (χ 2= 4.50 , P< 0.05 ) in Group ICT compared to 39% and 39% in Group CCT respectively. The differences were also confirmed statistically in the following aspects: the patients under 50 years with good recovery pronounced a number increase (χ 2= 7.54 , P< 0.01 ), while the mortality in the same range of age was decreased in Group ICT (χ 2= 5.28 , P< 0.05 ). The mortality was reduced significantly in patients with GCS for 6-8 on admission (χ 2= 8.47 , P< 0.01 ) and in patients with the level of brain stem injured bellow mesencephalon (χ 2= 4.15 , P< 0.05 ). ICT would improve the outcome in patients undergoing conservative therapy only (χ 2= 13.13 , P< 0.01 ). Conclusions: NIC plays an important role in assessing the neurological state, guiding management, evaluating curative effect and estimating the outcome.

Curative effect of wilsonii injecta on severe head injury

To study the curative effect of wil sonii injecta on severe head injury (SHI).Methods: A total of 120 patients with SHI were divided randomly into 2 groups, the patients treated with conventional methods as Group A (n=60) and the patients treated with wilsonii injecta as Group B (n=60). The changes o f neural function indexes were evaluated with Glasgow Coma Scale (GCS) before tr eatment and with Glasgow Outcome Scale (GOS) after treatment, simultaneously, th e parameters of hemorrheological indexes (HI), brain electrical activity map (BE AM) and transcranial Doppler sonography (TCD) were observed before and after tre atment.Results: In Group B, the clinical GCS, the HI, the BEAM and the prognosis GOS were improved much more than those in Group A. And the TCD parame ters in Group B decreased, which had significant difference compared with that i n Group A (P< 0.01 ).Conclusions: Wilsonii injecta can rapidly improve the injured p ersons’ conscious states, the abnormal BEAM and the surviving quality. It sugges ts that the improvement of the HI is related to the relief of the vasospasm of the arterial blood vessels in the brain, which may be one of the important mecha nisms of wilsonii injecta in improving the prognosis.

Effect of mild head injury on intelligence in Zahedan, Iran

Objective： To investigate the effects of mild head injury （HI） on the victims＇ intelligence by measuring their intelligence quotient （IQ）.Methods： This cohort study was performed in Khatamol-Anbia Hospital, Zahedan, Iran and the IQs of 30 mild HI patients were measured right after the injury （IQ0） and six months later （IQ6）. The IQs of 90 close relatives of the patients were also measured at the same period of time as the non-exposure group. The IQs were measured with Wechsler adult intelligence scale-revised （WAIS-R）. The IQ0, IQ6 and their differences （IQ change） were compared in HI patients and their relatives using the Student＇s t test.Results： The mean IQ0 of the HI patients was similar to their relatives. The IQ6 of HI patients appeared to be less than those of their relatives. Moreover, the IQ6 of the HI patients appeared to be less than their initial scores. HI was associated with more decrease in IQ6 compared with IQ0and the female subjects showed more decrease in IQ6 compared with their IQ0.Conclusion： HI seems to be associated with decrease in IQ six months after the injury and it is more evident in female HI patients.

Forensic medical study on morphology and formative mechanism of blunt head injury

Objective： To study the patterns and morphologic characteristics of blunt head injury and analyse its formative mechanism in attempt to provide references for medicolegal expertise. Methods： The statistical analysis was done in terms of gender, age, as well as the nature, pattern, location, and feature of the injuries. Results： Among the 202 cases of head injury-induced death, 124 were male and 78 female with the age ranging from 1-81 years. Death caused by homicide was dominant （106, 52.5%）, followed by suicide （49, 24.3%） and accident （44, 21.8%）. The majority of suicide-induced death were byfalling from height, and traffic crash was responsible for majority of unexpected death cases. The morphology and pathogenesis of the injuries varied according to differences on the mode, magnitude, and orientation of the outside force giving rise to blunt injury as well as the character of vulnerants. Conclusion： Studies on the morphology and its forma- tive rationale of blunt head injury will offer easy access to medicolegal expertise on the mode and character of the injury.

BRAIN INJURY BIOMECHANICS IN REAL WORLD VEHICLE ACCIDENT USING MATHEMATICAL MODELS

This paper aims at investigating brain injury mechanisms and predicting head injuries in real world accidents. For this purpose, a 3D human head finite element model （HBM-head） was developed based on head-brain anatomy. The HBM head model was validated with two experimental tests. Then the head finite element（FE） model and a multi-body system （MBS） model were used to carry out reconstructions of real world vehicle-pedestrian accidents and brain injuries. The MBS models were used for calculating the head impact conditions in vehicle impacts. The HBM-head model was used for calculating the injury related physical parameters, such as intracranial pressure, stress, and strain. The calculated intracranial pressure and strain distribution were correlated with the injury outcomes observed from accidents. It is shown that this model can predict the intracranial biomechanical response and calculate the injury related physical parameters. The head FE model has good biofidelity and will be a valuable tool for the study of injury mechanisms and the tolerance level of the brain.