Research progress on the relationship between m6A methylation modification and acute kidney injury / 实用医学杂志

Acute kidney injury(AKI)is a global public health problem with high morbidity,high mortality and costly treatment cost.The pathogenesis of AKI is very complex,and the treatment strategies for AKI are lim-ited,then it is very matter to explore the pathophysiological mechanism and potential therapeutic targets of acute kidney injury.N6-methyladenosine(m6A)is the most abundant and extremely conservative epigenetic modification in eukaryotic,which is a dynamic and reversible process involving in splicing,nuclear export,translation,stabil-ity,and higher structure of RNA,and regulated by three regulatory factors:methyltransferase,demethylase and methylated reading protein.Current studies have found that m6A plays an important regulatory role in AKI and can be a potential therapeutic target for AKI.In this review,we provide a brief description of m6A and summarize the impact of m6A on AKI and possible future study directions for this research.

Case report: A vertebral bone spur as an etiology for spinal cord herniation: case presentation, surgical technique, and review of the literature.

Objective: The pathophysiology of idiopathic spinal cord herniation remains unknown. However, several different factors have been postulated, such as congenital causes (ventral dura mater duplication, preexisting pseudomeningocele, or other congenital dural defects), inflammation, remote spinal trauma, or thoracic disc herniation. Herein, the diagnosis and surgical treatment of a patient with spinal cord herniation caused by an intraspinal bone spur is presented along with a relevant literature review. Case presentation: A 56-year-old male patient presented with a non-traumatic Brown-Sequard syndrome persisting for over 1 year. A magnetic resonance imaging of the spinal axis revealed a ventral spinal cord displacement in the level of T 6/7. A supplementary thin-sliced computed tomography of the spine revealed a bone spur at the same level. For neurosurgical intervention, T 6 and T 7 laminectomy was performed. The cranial and caudal end of the right paramedian ventral dural defect was visualized and enlarged. Following extradural spinal cord mobilization by denticulate ligament transection, the spinal cord was finally released. The spinal cord was rotated and the ventral closure of the dural defect was performed by continuous suture. The patient recovered from surgery without additional deficits. The patient's postoperative gait, sensory, and motor function deficits improved, and further neurological deterioration was prevented. Conclusion: Since the first description of spinal cord herniation by Wortzman et al. in 1974, approximately 260 cases have been reported in the literature. In addition to other causes, intraspinal bone spur is a possible cause of spinal cord herniation.

Research progress in the role of endoplasmic reticu-lum stress in cerebral ischemia-reperfusion injury / 中国药理学与毒理学杂志

During cerebral ischemia-reperfusion injury(CIRI),endoplasmic reticulum stress(ERS)leads to the development and progression of a series of deleterious physiological responses such as oxidative stress,dis-turbed calcium ion homeostasis,inflammation,apoptosis and autophagy.The unfolded protein response(UPR)is the main pathway activated by ERS,which regulates the expression of related factors within the endoplasmic reticu-lum(ER)and reduces protein translation levels.Prolonged and intense ERS may lead to cell death.Excessive ERS induces apoptosis mediated by C/EBP homologous pro-tein(CHOP),caspase-12 and c-Jun N-terminal kinase(JNK),thereby exacerbating brain damage.The thresh-old for the transition from adaptive mechanisms to apop-totic mechanisms during ERS depends on multiple fac-tors,including the cell status and environment,signaling pathway activity status,cumulative cascade,and the dose and time of ERS inducers.Further research is needed to completely elucidate the mechanism of ERS.Although the factors associated with the PERK and ATF6 path-ways are less extensively studied,their regulators still exist.Deficiency of protein tyrosine phosphatase 1B(PTP1B)leads to increased phosphorylation of PERK-eIF2α,while regulation of the proteasome and regulation of the XBP1 target gene WFS1 may also affect ATF6 sta-bility.In addition,differences in the structure,gene expres-sion,and metabolism of different types of neurons,as well as in their internal environment,may lead to differ-ences in their response to and impact on ERS.Differenc-es in UPR signaling pathways occur in hippocampal neurons and medial thalamic cells,and Purkinje cells and pyramidal cells may be more sensitive to ERS than other types of neurons.Our group's previous study found that ERS induced apoptosis in neurons after the onset of CIRI by regulating proteins such as GRP78,CHOP and caspase-12,but the effects of UPR activation on different cells need to be further investigated.

Inhibition of phosphodiesterase 4 attenuates aquapo-rin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury / 中国药理学与毒理学杂志

OBJECTIVE To investigate the role of PDE4 inhibition in astrocyte swelling caused by cerebral ischemic/reperfusion(I/R)injury and the molecular mech-anisms.METHODS SD rats were subjected to 2 h of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion(MCAO/R).Roflumilast(Roflu)was intraperitoneally injected 2 h after MCAO.At 24 h after reperfusion,a high-resolution MRI was performed and using the wet-dry weighting method to measure the water content.The oxygen-glucose deprivation/reoxygenation(OGD/R)model was established in primary astrocytes for 2 h.After 24 h of reoxygenation,CellMask? plasma membrane stain was used to label the plasma membrane to calculate cell volume.The protein expressions insides astrocytes and penumbra were detected by Western blot-ting.To investigate the role of Akt/FoxO3a in mediating the effect of Roflu on the expression of AQP4.The astro-cytes were treated with an Akt inhibitor MK2206 before treatment with Roflu and the activation of Akt,the expres-sion of AQP4 and cell volume were determined as described above.In addition,an IL-1β-stimulated cell model was established in astrocytes,the expression of AQP4 and the activation of Akt/FoxO3a were detected by Western blotting.The change of AQP4 expression inside astrocytes and penumbra were visualized by immunofluo-rescence staining.RESULTS Roflu reduced MCAO/R-induced water contents,the expression of AQP4 and the phsophorylation of Akt and FoxO3a in the brains of MCAO/R rats.Inhibition of PDE4 decreased the cell volume and the expression of AQP4 in primary astro-cytes subjected to OGD/R.PDE4 inhibition activated Akt/FoxO3a,and inhibition of Akt by MK2206 blocked the protective effect of Roflu against OGD/R induced astro-cyte swelling.PDE4B knocking down reduced the expres-sion of AQP4,while PDE4B overexpression reversed the effect of PDE4B siRNA in astrocytes.Roflu exert-ed similar protective effect in IL-1β-cultured astrocytes,and importantly overexpression of FoxO3a remarkably increased the expression of AQP4 in IL-1β-stimulated astrocytes.CONCLUSION Our findings indicate that PDE4 inhibition limits I/R-induced brain edema and astro-cyte swelling via the Akt/FoxO3a/AQP4 pathway.PDE4 inhibition is a promising strategy for the treatment of brain edema after I/R injury.

Intra-arterial injection of Diclofenac by informal health practitioner: A rare complication of a common drug.

Introduction and importance: Intra-arterial injections (IA) though rare, cause acute limb ischaemia with often catastrophic outcomes. Symptoms could progress rapidly and early identification and intervention could help in preventing the limb gangrene. Methodology: The work has been reported in line with the SCARE 2020 criteria:Agha RA, Franchi T, Sohrabi C, Mathew G, for the SCARE Group. The SCARE 2020 Guideline: Updating Consensus Surgical CAse REport (SCARE) Guidelines, International Journal of Surgery 2020; 84:226-230. Operative procedure was performed by consultant of general surgery. Case presentation: 38-year-old male presented to surgery casualty with history of sudden onset of pain and paraesthesia in the left forearm and palm followed by progressive weakness and discolouration, 15 hours following injection of Diclofenac in the mid cubital region. Clinical discussion: On examination, limb temperature was lower, finger movements were minimal. However, distal pulses were palpable, and duplex ultrasound showed normal triphasic flow. In view of the equivocal clinico-radiological findings, the patient underwent CT-Angiography of upper limb, which showed non-opacification of radial and ulnar arteries. Fasciotomy of forearm, brachial artery exploration and removal of embolus was attempted in a doubtful viable left upper limb. No thrombus was noted. Subsequently, he was managed conservatively, and cervical sympathectomy was done. As there was progressive deterioration in the viability of the limb, the patient underwent an above elbow amputation. Conclusion: Intra-arterial injections can lead to limb threatening gangrene, the course of which can be rapid A multidisciplinary team approach was necessary to arrive at a diagnosis and provide optimum care.

Dural repair with fat patch for idiopathic spinal cord herniation: operative technique and a review of seven cases.

Background: Idiopathic ventral thoracic spinal cord herniation is a rare disease presented with progressive myelopathy or Brown Séquard syndrome, causing neurological deficits. There is no consensus on etiology and surgical strategy. The purpose of the present study is to report the case series using fat patch for the repair of the ventral dural defect with clinical follow up. Methods: A retrospective review of all cases of idiopathic spinal cord herniation (ISCH) at our institution was performed between January 2017 and June 2021. Clinical data were reviewed including patients' demographic information, symptoms, imaging, operative details, perioperative and postoperative courses, and clinical outcomes, and complications. Japanese Orthopedic Association (JOA) score was calculated preoperatively and postoperatively for the comparison of outcomes. Results: A total of 7 patients were included. Fat patch was applied in all cases, and artificial dural patch was also used in 2 cases. Average operating time and estimated blood loss were 3 hours and 24 minutes and 88.6 mL, respectively. Five of 7 patients improved and 2 patients remained unchanged during follow up (average, 23.4 months; range, 9-42 months). The mean recovery rate (RR) of JOA score was 17.9%. One patient experienced cerebrospinal fluid (CSF) leakage, and 1 patient suffered from surgical related spinal canal stenosis. Conclusions: Surgical treatment using fat patch is an effective strategy for the ventral dural defect repair of ISCH.

Duplication of Ventral Dura as a Cause of Ventral Herniation of Spinal Cord-A Report of Two Cases and Review of the Literature.

BACKGROUND: Idiopathic spinal cord herniation (ISCH) is a treatable spinal disease. It is rare and often misdiagnosed, causing a delay in management. The etiology is multifactorial, with one of the causes being duplication of the ventral dura. The spinal cord herniates within this defect and becomes strangulated, causing neurological deficits. We report the duplication of a ventral spinal cord as an important cause of ISCH in our review. CASE DESCRIPTION: We present 2 cases of ISCH with duplication of the dura, including their relevant clinical and imaging features. The patients underwent surgical reduction of the herniated spinal cord with enlargement of the defect and placement of a dural substitute ventral to the cord. We have also reported the outcomes of the 2 patients, with an emphasis on the factors predictive of poor outcomes (i.e., long-standing symptoms, a delay in intervention, poor neurological status at presentation, and a thinned out atrophic spinal cord found during surgery). We also reviewed the available data for duplication of the dura with ISCH. CONCLUSIONS: Very few asymptomatic patients can be treated conservatively. The surgical outcomes have been favorable for symptomatic patients. Proper exposure, gentle manipulation while reducing the herniated spinal cord, enlargement of the defect, and the use of intraoperative monitoring will help limit the postoperative deficits. Duplication of the ventral dura is an important cause of ISCH. It prevents the formation of an anterior pseudomeningocele after surgery. Owing to the rarity of the disease and the lack of follow-up data with recurrence rates, it has not been possible to form clear guidelines for management.

Direct puncture for diagnosis of intradural spinal arachnoid cyst and fenestration using 3D rotational fluoroscopy: technical note and the "jellyfish sign".

The authors report on a 47-year-old woman with a symptomatic thoracic spinal arachnoid cyst (SAC) who underwent a novel procedure that involves direct puncture of the SAC to visualize, diagnose, and potentially treat these rare spinal lesions. The method described utilizes 3D fluoroscopy to gain access to the SAC, followed by injection of myelographic contrast into the cyst. A characteristic "jellyfish sign" was observed that represents the containment of the contrast within the superior aspect of the cyst and a clear block of cranial flow of contrast, resulting in an undulating pattern of movement of contrast within the cyst. Following balloon fenestration of the cyst, unimpeded flow of contrast was visualized cranially throughout the thoracic subarachnoid space. The patient was discharged the following day in good condition, and subsequently experienced 1 year free from symptoms. This is the first reported case of a successful direct puncture of an SAC with balloon fenestration, and the first noted real-time fluoroscopic "behavior" of CSF within an arachnoid cyst.

Spinal cord herniation repair with microstaples: case report.

Idiopathic spinal cord herniation (ISCH) is a relatively rare and frequently misdiagnosed condition. It preferentially affects women and causes progressive thoracic myelopathy that presents as a Brown-Séquard syndrome or as spastic paraparesis. Although its etiology and pathogenesis are controversial, ISCH is characterized by the presence of an anterior dural defect that allows the incarceration of a segment of the cord. Typically, a C-shaped ventral displacement and kinking of the cord are visible on sagittal MRI. Surgery aimed at stopping or reversing myelopathic symptoms is usually recommended for symptomatic patients. Surgical options include reduction of the hernia and direct suturing, or enlargement of the dural defect, with or without patching. Suturing under the cord in a very tight space can be troublesome and may lead to neurological deterioration. The authors present the case of a symptomatic ISCH in which nonpenetrating titanium microstaples were used to close the dural defect after cord reduction. The patient experienced a good outcome, and the follow-up MRI study showed adequate cord repositioning and stability of the suture. The use of microstaples, which allows for an easier and faster dural closure than conventional suturing, is a novel technical adjunct that has not been previously reported for this condition. In addition, microstaples produce minimal metallic artifact that does not hinder the quality of follow-up MR images.

Effects of Anisodine Hydrobromide on Cell Apoptosis and ERK1/2 Phosphorylation Level in Brain Tissue of Model Rats with Acute Cerebral Ischemia-reperfusion Injury / 中国药房

OBJECTIVE:To study the effects of anisodine hydrobromide on cell apoptosis and extracellular signal-regulated pro-tein kinase 1/2 (ERK1/2) phosphorylation (p-ERK1/2) level in brain tissue of model rats with acute cerebral ischemia-reperfusion injury. METHODS:Rats were randomly divided into sham operation group,model group,positive control group(nimodipine 1.0 mg/kg),anisodine hydrobromide high-dose,medium-dose,low-dose,extreme low-dose groups(1.2,0.6,0.3,0.15 mg/kg),8 in each group. Suture method was used to establish the rat models with acute cerebral ischemia-reperfusion injury. Rats were intrave-nously injected once in tail at 2nd of ischemia and 6th of reperfusion. Then adenosine triphosphate (ATP) enzyme activity,Ca2+content,cell apoptosis in brain tissue,p-ERK1/2 protein expression in brain tissue,and p-ERK1/2/total ERK1/2 (t-ERK1/2) pro-portion in brain tissue of rats were detected after 22 h of reperfusion. RESULTS:Compared with sham operation group,ATP en-zyme activity in brain tissue of rats in model group was obviously decreased,Ca2+ content was obviously increased,density of cell apoptosis in brain tissue was obviously increased,with statistical significances(P<0.01). Compared with model group,density of cell apoptosis in brain tissue was obviously decreased in each administration group;Ca2+ contents in brain tissue of rats in positive control group,anisodine hydrobromide high-dose,low-dose groups were obviously decreased;and p-ERK1/2/t-ERK1/2 proportion in brain tissue of rats in anisodine hydrobromide high-dose,low-dose,extreme low-dose groups were obviously increased,with sta-tistical significances(P<0.05 or P<0.01);the other differences were not statistically significant(P>0.05). CONCLUSIONS:An-isodine hydrobromide can inhibit the cell apoptosis in brain tissue of model rats with acute cerebral ischemia-reperfusion injury,andthe mechanism may be related with activating ERK1/2 signal pathway and regulating ATP enzyme activity to decrease the Ca2+content in the brain tissue.

Effects of Anisodine Hydrobromide on Cell Apoptosis and ERK1/2 Phosphorylation Level in Brain Tissue of Model Rats with Acute Cerebral Ischemia-reperfusion Injury / 中国药房

OBJECTIVE:To study the effects of anisodine hydrobromide on cell apoptosis and extracellular signal-regulated pro-tein kinase 1/2 (ERK1/2) phosphorylation (p-ERK1/2) level in brain tissue of model rats with acute cerebral ischemia-reperfusion injury. METHODS:Rats were randomly divided into sham operation group,model group,positive control group(nimodipine 1.0 mg/kg),anisodine hydrobromide high-dose,medium-dose,low-dose,extreme low-dose groups(1.2,0.6,0.3,0.15 mg/kg),8 in each group. Suture method was used to establish the rat models with acute cerebral ischemia-reperfusion injury. Rats were intrave-nously injected once in tail at 2nd of ischemia and 6th of reperfusion. Then adenosine triphosphate (ATP) enzyme activity,Ca2+content,cell apoptosis in brain tissue,p-ERK1/2 protein expression in brain tissue,and p-ERK1/2/total ERK1/2 (t-ERK1/2) pro-portion in brain tissue of rats were detected after 22 h of reperfusion. RESULTS:Compared with sham operation group,ATP en-zyme activity in brain tissue of rats in model group was obviously decreased,Ca2+ content was obviously increased,density of cell apoptosis in brain tissue was obviously increased,with statistical significances(P<0.01). Compared with model group,density of cell apoptosis in brain tissue was obviously decreased in each administration group;Ca2+ contents in brain tissue of rats in positive control group,anisodine hydrobromide high-dose,low-dose groups were obviously decreased;and p-ERK1/2/t-ERK1/2 proportion in brain tissue of rats in anisodine hydrobromide high-dose,low-dose,extreme low-dose groups were obviously increased,with sta-tistical significances(P<0.05 or P<0.01);the other differences were not statistically significant(P>0.05). CONCLUSIONS:An-isodine hydrobromide can inhibit the cell apoptosis in brain tissue of model rats with acute cerebral ischemia-reperfusion injury,andthe mechanism may be related with activating ERK1/2 signal pathway and regulating ATP enzyme activity to decrease the Ca2+content in the brain tissue.

Experimental studies of ischemia postconditioning alleviated lung injury after limb ischemia reperfusion in rats / 天津医药

Objective To observe the effects of ischemic postconditioning (I-postC) on lung injury after limb ischemia reperfusion (LIR) in rats, and to investigate the protective effect and the mechanisms. Methods Twenty-four Wistar rats were divided into three groups:control group (group Control), ischemia-reperfusion group (group IR) and ischemic postcondi?tioning group (group I-postC). Referring to routine method in our department, the model rats underwent 4-hour ischemia and 4-hour reperfusion of hind limbs were made. In group Control, the rubber band around the limb was loose,which did not block the blood flow. Rats in group I-postC were given repeated 3 times of 5 min ischemia-5 min reperfusion, and then did perfusion 4 h before reperfusion. The blood and lung samples were collected for detecting arterial gas of partial pressure of oxygen [p(O2)] and partial pressure of carbon dioxide [p(CO2)]. The plasma and lung tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD) and xanthine oxidase (XOD) were detected. The morphological changes of lung tissue were ob?served under light microscope and electron microscope. Results It was found that after suffering from ischemia-reperfu?sion, levels of p(O2) and p(CO2) decreased significantly. The activity of SOD in plasma and lung tissues decreased, but XOD and MDA increased significantly (P<0.05). With microscope, lung interstitial vascular dilation, infiltration of neutrophils, the width of the alveolar space, alveolar septal thickening and alveolar exudate were found. Compared with IR group, it was found that p(O2) and p(CO2) increased significantly in group I-postC. The activity of SOD in plasma and lung tissues in?creased, but XOD and MDA decreased significantly(P<0.05). The mild damage of pathological changes were found. Conclu?sion Ischemic postconditioning can reduce the lung injury after limb ischemia reperfusion in rats, which may be related to the inhibition of lipid peroxidation.

Idiopathic spinal cord herniation: an imaging diagnosis with a significant delay.

BACKGROUND CONTEXT: Idiopathic spinal cord herniation (ISCH) is an underrecognized entity that is often underappreciated by the neurosurgery and neuroradiologic communities. This leads to delayed diagnosis, multiple imaging studies, other diagnostic tests, inappropriate surgeries, and repeat office visits. PURPOSE: To evaluate common associations between ISCH and patient demographics/clinical presentation and to analyze the potential for delayed diagnosis. PATIENT SAMPLE: Patient sample included those diagnosed with ISCH on imaging at our institution from June 20, 2005 to December 3, 2012. OUTCOME MEASURES: These were based on the patient improvement/stability/decline based on the patients' most recent clinic/office visit when compared with initial presentation. METHODS: A retrospective search of radiology reports was performed using Illuminate software from June 20, 2005 to December 3, 2012, using the search term "idiopathic spinal cord herniation." Clinical data were reviewed including patient's age, sex, presenting clinical symptoms, number and type of imaging studies performed as part of the workup, other diagnostic tests, pain procedures, surgeries, and time between original presentation and diagnosis of ISCH on imaging. RESULTS: A total of 55 patients had the search term "idiopathic spinal cord herniation" included in their radiology report, of which 37 patients were found to meet the imaging and clinical diagnosis of ISCH. The median time from presentation to imaging diagnosis was 20 months in patients younger than 60 years and 5 months in those 60 years or older (p=.02). Of the 37 patients evaluated, 27 (73%) had no change in symptoms, 5 patients (14%) experienced worsening of symptoms, and 5 (14%) experienced symptom improvement from original presentation to most recent office visit. Among all patients evaluated, three underwent repair of the ventral dural defect in ISCH, resulting in clinical improvement. There was a median of nine outpatient office visits, three magnetic resonance images (MRIs), and one electromyography (EMG) per patient presenting with ISCH. The most frequent complaints were neck/upper back pain in 70%, upper/lower extremity numbness/paresthesias/weakness in 49%, hyperreflexia in 22%, and burning chest pain in 22%. CONCLUSIONS: Prolonged time to diagnosis and subsequent treatment of ISCH protracts patient symptoms and is associated with redundant diagnostic tests and patient visits. Earlier use of MRI in younger patients (younger than 60 years) may be warranted in those with a clinical presentation suggestive of Brown-Sequard symptomatology. Increasing recognition of ISCH in imaging and surgical communities would lead to improved patient care.

Effects of morphine preconditioning- postconditioning on ischemia-reperfusion injury in isolated rat hearts / 中华麻醉学杂志

Objective To evaluate the effects of morphine preconditioning-postconditioning on ischemia-reperfusion (I/R) injury in isolated rat hearts. Methods Male SD rats weighing 180-200 g were killed after intraperitoneal injection of heparin 500 U/kg. The hearts were immediately removed and perfused in a Langendorff apparatus with K-H solution gassed with 95%O2-5%CO2 .HR and left ventricular systolic pressure (LVSP) were measured from a fluid-filled latex balloon in the left ventricle. Global myocardial ischemia was induced by interrupting perfusion for 45 min followed by 60 min reperfusion. Forty isolated rat hearts were randomly divided into 5 groups (n = 8 each): group 1 (I/R); group II morphine preconditioning (M1 ); group Ⅲ morphine postconditioning (M2); group IV M1 + M2; group V 5-hydroxydecanoate (5-HD) + M2. Group M1 was perfused with K-H solution containing morphine 3.0 μmol/L for 20 min 30 min before ischemia followed by 10 min normal K-H solution perfusion. Group M2 was perfused with K-H solution containing morphine 3.0 μmol/L for 10 min at the beginning of reperfusion followed by 50 min normal K-H solution perfusion. Group 5-HD + M2 was perfused with K-H solution containing morphine 3.0 μmol/L+ 5-HD 10-4 mmol/L for 10 min at the beginning of reperfusion followed by 50 min normal K-H solution perfusion. Myocardial CK-MB activity was measured and myocardial infarct size (IS/AAR) detennined (by 2,3,5-triphenyl tetrazolium staining) at the end of 60 min reperfusion. Results The preconditioning, postconditioning and combination of preconditioning and postconditioning with morphine 3.0 μmol/L perfusion for 10 min all provided cardio-protective effects in terms of IS/AAR and myocardial activation of CK-MB. Conclusion Although the combination of morphine preconditioning and postconditioning can protect the heart against I/R injury, the effects are similar to those of either of them alone, and the reason may be that either of them alone protects the heart against I/R injury via activating mitoKATP .