Neurovascular Repair Research Articles

Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

Abstract TP310: Prnd in Angiogenic Brain Endothelial Cells is Involved in Neurovascular Repair After Ischemic Stroke

Introduction: The prion protein family member doppel (encoded by the Prnd gene) is essential for the control of angiogenesis during CNS development and has been implicated in pathological angiogenesis. Various data demonstrate that Prnd expression is linked to physiological angiogenesis by regulating VEGFR2 signaling. However, the roled for Prnd in pathological angiogenesis after ischemic stroke is not known. Therefore, we hypothesized that Prnd contributes to stroke-induced brain injury repair by regulating angiogenesis. Methods: We induced ischemic injury in Prnd+/+ and Prnd-/- mice by middle cerebral artery occlusion for 30 minutes. Infarct volume was measured three days and 28 days after stroke and survival rates were analyzed. We also measured the expression of Prnd and angiogenesis-related factors (VEGF, VEGFR2, and VE-Cadherin) in control and Prnd-/- brains. We also determined the activation and localization of pericytes, oligodendrocytes, and astrocytes in brain sections after ischemic stroke. Results: Prnd-/- mice showed worse survival rate than Prnd+/+ mice after ischemic stroke. At three days post-stroke, infarct volume in Prnd-/- and Prnd+/+ mice was similar, but brain infarct volume of Prnd-/- mice was increased at 28 days. Interestingly, Prnd mRNA levels were significantly increased in the ipsilateral region of the brain of Prnd+/+ mice at three days post ischemic stroke. VEGFR2 mRNA expression increased in the Prnd+/+ brain, but this increase was observed to a higher extent in the Prnd-/- brain. Also, the levels of VE-Cadherin which is an essential component of adherens junctions and modulates the VEGFR function in Prnd+/+ was increased in the ipsilateral region compared to contralateral, but not in Prnd-/-mice. Conclusion: Our results indicate that Prnd deficiency is associated with poor stroke outcome and that increased Prnd expression after ischemic stroke is involved in brain injury repair by regulating angiogenesis-related signaling pathways. The data also suggest that Prnd-controlled angiogenesis may be a potential mechanism to improve outcomes after ischemic stroke.

Buyang Huanwu Decoction promotes neurovascular remodeling by modulating astrocyte and microglia polarization in ischemic stroke rats

Ethnopharmacological relevanceBuyang Huanwu Decoction (BYHWD), one of the most commonly utilized traditional Chinese medicine prescription for treatment of cerebral ischemic stroke. However, the understanding of BYHWD on neurovascular repair following cerebral ischemia is so far limited. Aim of the studyThis research investigated the influence of BYHWD on neurovascular remodeling by magnetic resonance imaging (MRI) technology and revealed the potential neurovascular repair mechanism underlying post-treatment with BYHWD after ischemic stroke. Materials and methodsMale Sprague–Dawley rats were utilized as an ischemic stroke model by permanent occlusion of the middle cerebral artery (MCAO). BYHWD was intragastrically administrated once daily for 30 days straight. Multimodal MRI was performed to detect brain tissue injuries, axonal microstructural damages, cerebral blood flow and intracranial vessels on the 30th day after BYHWD treatment. Proangiogenic factors, axonal/synaptic plasticity-related factors, energy transporters and adenosine monophosphate-activated protein kinase (AMPK) signal pathway were evaluated using western blot. Double immunofluorescent staining and western blot were applied to evaluate astrocytes and microglia polarization. ResultsAdministration of BYHWD significantly alleviated infarct volume and brain tissue injuries and ameliorated microstructural damages, accompanied with improved axonal/synaptic plasticity-related factors, axonal growth guidance factors and decreased axonal growth inhibitors. Meanwhile, BYHWD remarkably improved cerebral blood flow, cerebral vascular signal and promoted the expression of proangiogenic factors. Particularly, treatment with BYHWD obviously suppressed astrocytes A1 and microglia M1 polarization accompanied with promoted astrocyte A2 and microglia M2 polarization. Furthermore, BYHWD effectively improved energy transporters. Especially, BYHWD markedly increased expression of phosphorylated AMPK, cyclic AMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) accompanied by inactivation of the NF-κB. ConclusionTaken together, these findings identified that the beneficial roles of BYHWD on neurovascular remodeling were related to AMPK pathways -mediated energy transporters and NFκB/CREB pathways.

Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1

Cerebral small vessel disease (cSVD) constitutes a major risk factor for dementia. Monocytes play important roles in cerebrovascular disorders. Herein, we aimed to investigate the contribution of non-classical C-X3-C motif chemokine receptor (CX3CR)1 monocytes to cSVD pathobiology and therapy. To this end, we generated chimeric mice in which CX3CR1 in non-classical monocytes was either functional (CX3CR1GFP/+) or dysfunctional (CX3CR1GFP/GFP). cSVD was induced in mice via the micro-occlusion of cerebral arterioles, and novel immunomodulatory approaches targeting CX3CR1 monocyte production were used. Our findings demonstrate that CX3CR1GFP/+ monocytes transiently infiltrated the ipsilateral hippocampus and were recruited to the microinfarcts 7 days after cSVD, inversely associated with neuronal degeneration and blood-brain barrier (BBB) disruption. Dysfunctional CX3CR1GFP/GFP monocytes failed to infiltrate the injured hippocampus and were associated with exacerbated microinfarctions and accelerated cognitive decline, accompanied with an impaired microvascular structure. Pharmacological stimulation of CX3CR1GFP/+ monocyte generation attenuated neuronal loss and improved cognitive functions by promoting microvascular function and preserving cerebral blood flow (CBF). These changes were associated with elevated levels of pro-angiogenic factors and matrix stabilizers in the blood circulation. The results indicate that non-classical CX3CR1 monocytes promote neurovascular repair after cSVD and constitute a promising target for the development of new therapies.

MP02-07 REVISED PENIS SCORING CRITERIA: A MULTILINGUAL SYSTEMATIC REVIEW OF PENILE AMPUTATION AND REPLANTATION

You have accessJournal of UrologyCME1 Apr 2023MP02-07 REVISED PENIS SCORING CRITERIA: A MULTILINGUAL SYSTEMATIC REVIEW OF PENILE AMPUTATION AND REPLANTATION Aimee Tran, Bruno Machado, Nickolas Scherzer, Kennedy Kuykendall, Horace Spencer, Wael Almajed, Norman Saghir, Reyan Saghir, and Wayne Hellstrom Aimee TranAimee Tran More articles by this author , Bruno MachadoBruno Machado More articles by this author , Nickolas ScherzerNickolas Scherzer More articles by this author , Kennedy KuykendallKennedy Kuykendall More articles by this author , Horace SpencerHorace Spencer More articles by this author , Wael AlmajedWael Almajed More articles by this author , Norman SaghirNorman Saghir More articles by this author , Reyan SaghirReyan Saghir More articles by this author , and Wayne HellstromWayne Hellstrom More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003213.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Penile amputation can cause severe physical and psychosocial distress and, if feasible, warrants prompt replantation. Since the advent of microsurgery, its superiority over surgical repair for penile replantation has been presumed. However, this has been difficult to verify given the paucity of penile amputation publications compounded with inconsistent thorough reporting. The purpose of this study was to produce an updated systematic review of penile replantation, substantiated by the largest sample size to date, and to appraise the comparative value of the novel PENIS Score. METHODS: A systematic review identified 122 microsurgical and 40 surgical cases of penile replantation that qualified for review. The novel PENIS Score, which was modified to increase its utility and reproducibility, stratified penile amputations based on five criteria: position along the shaft, extension through the penis, neurovascular repair, ischemia time/type, and severed edge condition/contamination. Each individual PENIS criteria was then evaluated for association with short-term postoperative complications as well as erection, urination, and sensation. RESULTS: The viability of microsurgical and surgical replantation was equivalent at 92% and 94%, respectively. A statistically significant correlation was found between microsurgical repair and the return of sensation, though this did not correlate with nerve repair. While the return of sensation with nerve repair was 51%, comparable to microsurgical replantation without nerve repair at 42%, both were significantly higher than the 14% found in surgical replantation. There was a significant correlation noted between the extension of the amputation and severity of postoperative complications in microsurgical replantations (τ=.2649, p=.0126) not observed with surgical replantation. Preservation of a skin bridge was associated with a 40% reduction in severe postoperative complications, regardless of surgical method. CONCLUSIONS: Microsurgical replantation is superior in the return of sensation, with or without nerve repair. When faced with a situation in which no microsurgical expertise is available, surgical replantation is an appropriate alternative. Implementing the PENIS Score will help guide future case reports and systematic reviews. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e13 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Aimee Tran More articles by this author Bruno Machado More articles by this author Nickolas Scherzer More articles by this author Kennedy Kuykendall More articles by this author Horace Spencer More articles by this author Wael Almajed More articles by this author Norman Saghir More articles by this author Reyan Saghir More articles by this author Wayne Hellstrom More articles by this author Expand All Advertisement PDF downloadLoading ...

The Revised PENIS Score and proposal of the PACKAGE Checklist: a meta-epidemiologic study on penile amputation and replantation.

Penile amputation causes severe physical and psychosocial distress. Microsurgical implementation in penile replantation is presumed to be superior to surgical repair. This assumption has been difficult to verify. The purpose of this study was threefold: (1) to produce an updated review of penile replantation, substantiated by the largest sample size to date; (2) to appraise the comparative value of the novel PENIS Score and propose the PACKAGE Checklist, a guide for standardization of future case reports and reviews; and (3) to improve confusing terminology and recommend the standardization of vocabulary. A literature review assessed 432 full-text case reports in 20 languages and identified 123 microsurgical and 40 surgical cases of penile replantation. The novel PENIS Score stratified penile amputations based on 5 criteria: position along the shaft, extension through the penis, neurovascular repair, ischemia time and type, and severed edge condition and contamination. For the outcome measurements, a Kendall tau coefficient evaluated the association between each PENIS criterion for short-term postoperative complications and 3 outcome measures: erection, urination, and sensation. Less than half of surgical reports on penile replantation are sufficiently detailed to complete all PENIS Score criteria. The viability of microsurgical and surgical replantation was equivalent at 92% and 94%, respectively. A statistically significant correlation was found between microsurgical repair and the return of sensation but not with nerve repair. Return of sensation with nerve repair was 51%, and microsurgical replantation without nerve repair was 42%; both were significantly higher than the 14% for surgical replantation. Preservation of a skin bridge was associated with a 40% reduction in severe postoperative complications. Microsurgical replantation is superior in return of sensation, with or without nerve repair. Implementing the PACKAGE Checklist and PENIS Score will help inform case reports and reviews.

Immediate Combined Hand Reconstruction in a Patient with Complex Tissue Defect and Total Finger Amputation

Clinical evaluation of bones, tendons, joints, vessels, nerves and muscles at the patient's first presentation plays a critical role in determining the reconstruction plan of injured hand. In crush injury, skeletal stabilization forms the foundation for the entire reconstruction plane. In the basic approach, debridement of devitalized tissues, bone fracture stabilization, neurovascular repair, graft and flap coverage of critical tissues are applied respectively. In certain circumstances ectopic replantation can be an option in severely crushed injuries. Here in, we present the combined immediate reconstruction process of a patient applied with soft tissue defect in the hyposthenia region of the left hand, bony defect of the 4th and 5th metacarpals and total amputation of the 5th finger

Cerium oxide nanoparticles with antioxidative neurorestoration for ischemic stroke

Oxidative stress and mitochondrial damage are the main mechanisms of ischemia-reperfusion injury in ischemic stroke. Herein, cerium oxide nanoparticles with powerful free radical scavenging ability were used as carriers to load dl-3-n-butylphthalide (NBP–CeO2 NPs) for the combined treatment of ischemic stroke. NBP-CeO2 NPs could eliminate reactive oxygen species (ROS) in mouse brain microvascular endothelial cells and hippocampal neurons after oxygen-glucose deprivation/reoxygenation (OGD/R), and also save mitochondrial membrane potential, morphology, and function, thus alleviating the in vitro blood brain barrier (BBB) disruption and neuronal apoptosis. In the middle cerebral artery embolization/recanalization (MCAO/R) mouse model, the NBP-CeO2 NPs also possessed superior ROS scavenging ability, protected mitochondria, and preserved BBB integrity, thereby reducing cerebral infarction and cerebral edema and inhibiting neuroinflammation and neuronal apoptosis. The long-term neurobehavioral tests indicated that the NBP-CeO2 NPs significantly improved sensorimotor function and spatial learning ability by promoting angiogenesis after ischemic stroke. Therefore, the NBP-CeO2 NPs provided a novel therapeutic approach for ischemic stroke by combining antioxidant and neurovascular repair abilities, highlighting its wide application in ischemia-reperfusion injury.

Janus Faced HMGB1 and Post-Aneurysmal Subarachnoid Hemorrhage (aSAH) Inflammation.

Aneurysmal subarachnoid hemorrhage (aSAH), resulting majorly from the rupture of intracranial aneurysms, is a potentially devastating disease with high morbidity and mortality. The bleeding aneurysms can be successfully secured; however, the toxic and mechanical impact of the blood extravasation into the subarachnoid space damages the brain cells leading to the release of different damage-associated molecular pattern molecules (DAMPs). DAMPs upregulate the inflammation after binding their cognate receptors on the immune cells and underlies the early and delayed brain injury after aSAH. Moreover, these molecules are also associated with different post-aSAH complications, which lead to poor clinical outcomes. Among these DAMPs, HMGB1 represents a prototypical protein DAMP that has been well characterized for its proinflammatory role after aSAH and during different post-aSAH complications. However, recent investigations have uncovered yet another face of HMGB1, which is involved in the promotion of brain tissue remodeling, neurovascular repair, and anti-inflammatory effects after SAH. These different faces rely on different redox states of HMGB1 over the course of time after SAH. Elucidation of the dynamics of these redox states of HMGB1 has high biomarker as well as therapeutic potential. This review mainly highlights these recent findings along with the conventionally described normal role of HMGB1 as a nuclear protein and as a proinflammatory molecule during disease (aSAH).

Inhibition of Ferroptosis Using UAMC‐3203 in the Post‐stroke Period Does Not Impact Cognitive Outcomes in Diabetic Rats

IntroductionPost‐stroke cognitive impairment (PSCI) contributes to significant long‐term disability in stroke victims. 30% of ischemic stroke victims in the United States also have diabetes, which increases the risk of hemorrhagic transformation as well as PSCI. Ferroptosis, an iron‐induced cell death can instigate increased oxidative stress and contribute to impaired neurovascular repair leading to PSCI in diabetes. In our previous studies, we were able to identify that treating diabetic animals with an iron chelator, deferoxamine (DFX), prevents post‐stroke vasoregression and improves functional outcomes. Furthermore, DFX prevented the activation of ferroptosis in brain microvascular endothelial cells in vitro. Untreated diabetic animals experienced progressive cognitive decline while being monitored for 8 weeks. These findings led us to speculate that endothelial ferroptosis also plays a role in vasoregression and impacts cognitive outcomes post‐stroke. Therefore, this study was designed to test the hypothesis that inhibiting ferroptosis in the post‐stroke period will improve cognitive recovery in diabetic animals.MethodsAnimals were housed in reverse light cycle. 8 weeks after diabetes onset, male rats underwent 60 min middle cerebral artery occlusion (MCAO). On Day 3, after stroke injury was confirmed by MRI, animals were randomized to UAMC‐3 (2mg/kg) or vehicle treatment for 2 weeks. Sensorimotor and cognitive behavioral tests were performed during the animals’ active hours up to 8 weeks post MCAO.Results(Table 1): 60 min occlusion caused significant acute neurological deficits. There were no differences between the groups in indices measured by novel object recognition (NOR), Y‐maze and sucrose preference tests. Interestingly, step through latency in passive avoidance test (PAT) was lower in the UAMC‐3203 group.ConclusionTreatment with a ferroptosis inhibitor for 2 weeks after stroke did not impact recognition and working memory but worsened aversive learning in diabetic male rats. Unlike our previous study in which behavior tests were performed during rats’ passive hours, there was no progressive cognitive decline in untreated animals. Further evaluation of behavior testing times as well as tissue markers of neurovascular degeneration, inflammation and ferroptosis are required to determine whether molecular and cellular markers are affected by the treatment before overt changes in behavioral outcomes.

Traumatic penile partial amputation caused by rubber band a case report.

Introduction and importanceTraumatic amputation of the penis is a rare surgical emergency. Penile amputation is usually caused by self-mutilation, accidents, circumcision, assault and animal attacks. Accidental injury covers a large portion of external genitalia trauma because of its high prevalence and severity of this disease. Here, we report the case of a 21-year-old man who underwent replantation of his self-inflicted partial amputated penis.Case presentationWe report a case of traumatic penile partial amputation in a 21-year-old man with a history of mental retardation that presented with a one-day history of pain on the penile shaft due to tied penile shaft with a rubber band ten days prior. Genitalia examination showed a partial amputation at the penis shaft region. Reconstruction microsurgery and debridement on the penile shaft and urethral anastomosis were performed. This case highlights the management of traumatic penile partial amputation. The urethral anastomosis and penile replantation were successfully done.Clinical discussionPenile amputation is a rare urological emergency. Most of the cases reported with self-mutilation are a result of severe substance-induced psychosis or underlying psychiatric disorder. Factors that contribute to the successful penile replantation include the severity of the penile injury or amputation, type and mechanism of injury, team expertise available, duration of ischemia time, and use of a microscope at the time of neurovascular bundle repair.ConclusionA traumatic penile partial amputation is a rare urologic emergency. Self-inflicted amputation is often found in a patient with a history of psychological or mental illness. The limited data on detailed best surgical measures and outcomes is still a concern.

Neurovascular unit protection—novel therapeutic targets and strategies

Neurovascular unit protection—novel therapeutic targets and strategies

Neurovascular Unit: A critical role in ischemic stroke.

Ischemic stroke (IS), a common cerebrovascular disease, results from a sudden blockage of a blood vessel in the brain, thereby restricting blood supply to the area in question, and making a significantly negative impact on human health. Unfortunately, current treatments, that are mainly based on a recanalization of occluded blood vessels, are insufficient or inaccessible to many stroke patients. Recently, the profound influence of the neurovascular unit (NVU) on recanalization and the prognosis of IS have become better understood; in‐depth studies of the NVU have also provided novel approaches for IS treatment. In this article, we review the intimate connections between the changes in the NVU and IS outcomes, and discuss possible new management strategies having practical significance to IS. We discuss the concept of the NVU, as well as its roles in IS blood‐brain barrier regulation, cell preservation, inflammatory immune response, and neurovascular repair. Besides, we also summarize the influence of noncoding RNAs in NVU, and IS therapies targeting the NVU. We conclude that both the pathophysiological and neurovascular repair processes of IS are strongly associated with the homeostatic state of the NVU and that further research into therapies directed at the NVU could expand the range of treatments available for IS.

The role of peripheral monocytes and macrophages in ischemic stroke.

After acute ischemic stroke (AIS), peripheral monocytes infiltrate into the lesion site within 24h, peak at 3 to 7days, and then differentiate into macrophages. Traditionally, monocytes/macrophages (MMs) are thought to play a deleterious role in AIS. Depletion of MMs in the acute phase can alleviate brain injury induced by ischemia. However, several studies have shown that MMs have anti-inflammatory functions, participate in angiogenesis, phagocytose necrotic neurons, and promote neurovascular repair. Therefore, MMs play dual roles in ischemic stroke, depending mainly upon the MM microenvironment and the window of time post-stroke. Because activated microglia and MMs are similar in morphology and function, previous studies have often investigated them together. However, recent studies have used special methods to distinguish MMs from microglia and have found that MMs have properties which differ from microglia. Here, we review the unique role of MMs and the interaction between MMs and neurovascular units, including neurons, astrocytes, microglia, and microvessels. Future therapeutics targeting MMs should regulate the polarization and subset transformation of the MMs at different stages of AIS rather than comprehensively suppressing MM infiltration and differentiation. In addition, more studies are needed to elucidate the cellular and molecular mechanisms of MM subsets and polarization during ischemic stroke.

Secretion of proteins and antibody fragments from transiently transfected endothelial progenitor cells.

In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, neuroinflammation can lead to blood‐brain barrier (BBB) breakdown. After intravenous or intra‐arterial injection into mice, endothelial progenitor cells (EPCs) home to the damaged BBB to promote neurovascular repair. Autologous EPCs transfected to express specific therapeutic proteins offer an innovative therapeutic option. Here, we demonstrate that EPC transfection by electroporation with plasmids encoding the reporter protein GFP or an anti‐β‐amyloid antibody fragment (Fab) leads to secretion of each protein. We also demonstrate the secreted anti‐β‐amyloid Fab protein functions in β‐amyloid aggregate solubilization.

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

Microglia, the major endogenous immune cells of the central nervous system, mediate critical degenerative and regenerative responses in ischaemic stroke. Microglia become “activated”, proliferating, and undergoing changes in morphology, gene and protein expression over days and weeks post-ischaemia, with deleterious and beneficial effects. Pro-inflammatory microglia (commonly referred to as M1) exacerbate secondary neuronal injury through the release of reactive oxygen species, cytokines and proteases. In contrast, microglia may facilitate neuronal recovery via tissue and vascular remodelling, through the secretion of anti-inflammatory cytokines and growth factors (a profile often termed M2). This M1/M2 nomenclature does not fully account for the microglial heterogeneity in the ischaemic brain, with some simultaneous expression of both M1 and M2 markers at the single-cell level. Understanding and regulating microglial activation status, reducing detrimental and promoting repair behaviours, present the potential for therapeutic intervention, and open a longer window of opportunity than offered by acute neuroprotective strategies. Pharmacological modulation of microglial activation status to promote anti-inflammatory gene expression can increase neurogenesis and improve functional recovery post-stroke, based on promising preclinical data. Cell-based therapies, using preconditioned microglia, are of interest as a method of therapeutic modulation of the post-ischaemic inflammatory response. Currently, there are no clinically-approved pharmacological options targeting post-ischaemic inflammation. A major developmental challenge for clinical translation will be the selective suppression of the deleterious effects of microglial activity after stroke whilst retaining (or enhancing) the neurovascular repair and remodelling responses of microglia.

Abstract 110: RNA Sequencing Reveals Novel Macrophage Transcriptome Favoring Neurovascular Plasticity After Ischemic Stroke

Introduction: Blood monocytes/macrophages (MΦ) infiltrate the brain in massive numbers after ischemic stroke, but their functional roles in the post-stroke brain remain elusive. Methods: We sorted CD11b + CD45 high monocytes/MΦ from mouse blood and brain 5d after distal MCAO (dMCAO) and investigated their transcriptomic profiles by RNA-seq (n=3/group). Results: Robust genomic changes occurred in MΦ invading the post-dMCAO brain compared to their counterparts in the blood (3196 differentially expressed genes with >2 fold changes; FDR<0.05). In addition to their canonical role in immune responses, brain MΦ expressed unique transcriptomic programs which may favor post-stroke neurovascular repair. Functional enrichment analysis of brain MΦ transcriptome revealed significant overrepresentation (p<0.01) of 110 biological processes linked to neurovascular remodeling and plasticity (e.g., angiogenesis and axonal regeneration), suggesting a previously underappreciated role for MΦ in post-stroke brain repair. Upstream Regulator analysis predicted PPARγ as a master regulator (z-score=2.64, p<10 -15 ) that drives the transcriptional reprogramming in post-stroke brain MΦ and dictates their functional phenotype. Accordingly, tamoxifen-induced, myeloid cell-specific PPARγ knockout mice demonstrated less post-stroke angiogenesis (BrdU+CD31 staining) and neurogenesis (BrdU+NeuN) than WT mice (n=9/group, p<0.01), which correlated significantly with the exacerbation of neurological deficits in these mice (n=9/group, p<0.01 vs WT in foot fault and adhesive removal tests) at 35d after dMCAO. Conclusions: Our study reveals a novel repair-enhancing transcriptome in brain MΦ during post-stroke neurovascular remodeling. As a master molecule controlling genomic reprogramming, PPARγ is a rational therapeutic target for promoting beneficial MΦ functions, and facilitating neurorestoration and long term functional recovery after ischemic stroke.

Induced membrane technique and microsurgery for open leg fractures of Gustilo types IIIB-C

Objective To evaluate the induced membrane technique combined with microsurgery for repair of open leg fractures of Gustilo types ⅢB-C. Methods This retrospective study reviewed 15 patients who had been treated for open leg fractures of Gustilo types ⅢB and ⅢC by the induced membrane technique and microsurgery between January 2015 and January 2017 at Institute of Orthopedics, 920 Hospital, The Joint Logistic Service of The People’s Liberation Army. They were 10 men and 5 women, aged from 18 to 41 years(average 32 years). There were 9 cases of Gustilo type IIIB and 6 ones of Gustilo type IIIC. After thorough debridement, the fractures were reduced and fixated temporarily using external frames. The bone defects were filled with antibiotic bone cement to induce biofilm formation. After necessary reconstruction of limb structures, including neurovascular repair and transposition of tendon and nerve, crucial soft-tissue wounds were covered with surgical flaps. In the secondary surgery 6 to 8 weeks later, with the external frames replaced by internal fixation or not, the bone cement was removed without damaging the biofilm before graft reconstruction with autogenous cancellous bone. Results The 15 legs were all salvaged successfully. The in-hospital time ranged from 21 to 39 days (mean, 29 days). Crucial wounds were repaired primarily without any severe or persistent infection. Follow-ups ranged from 12 to 24 months (average, 15 months). Bone union time ranged from 10 to 17 months (average, 11.2 months) with satisfactory aesthetic and functional recovery of the leg. Conclusion Reconstruction of open leg fractures of Gustilo types Ⅲ B-C with induced membrane technique and microsurgery can result in decreased therapeutic duration, reduced complications and positive outcomes. Key words: Fractures, open; Surgical flaps; Microsurgery; Leg; Induced membrane technique

Potential Immunotherapeutic Targets on Myeloid Cells for Neurovascular Repair After Ischemic Stroke

Neurological deficits and cognitive dysfunctions caused by acute ischemic stroke pose enormous burden to the stroke families and the communities. Restoration of the normal function of the neurovascular unit following ischemic stroke is critical for improving neurological recovery and cognitive functions after stroke. Recent evidence suggests that the myeloid cells including both the resident microglia and infiltrating monocytes/macrophages and neutrophils are highly plastic in response to the environmental cues. They intimately interact with multiple components of the neurovascular unit in response to the alarmins, danger associated pattern molecules (DAMPs) and other signals released from the ischemic brain. The aim of this review is to discuss the reciprocal interactions between the myeloid cells and the ischemic neurovascular unit during the late repair phase of cerebral ischemic stroke. We also summarize potential immunotherapeutic targets on myeloid cells and new therapeutic approaches targeting myeloid cells, such as cell transplantation, mitochondrial dynamic and extracellular vesicles-based therapy et al to enhance neurovascular repair for better stroke recovery.

SRμCT Reveals 3D Microstructural Alterations of the Vascular and Neuronal Network in a Rat Model of Chronic Compressive Thoracic Spinal Cord Injury.

The complex pathology of chronic thoracic spinal cord compression involves vascular and neuroarchitectural repair processes that are still largely unknown. In this study, we used synchrotron radiation microtomography (SRμCT) to quantitatively characterize the 3D temporal-spatial changes in the vascular and neuronal network after chronic thoracic spinal cord compression in order to obtain further insights into the pathogenesis of this disease and to elucidate its underlying mechanisms. Direct 3D characterization of the spinal cord microvasculature and neural microstructure of the thoracic spinal cord was successfully reconstructed. The significant reduction in vasculature and degeneration of neurons in the thoracic spinal cord visualized via SRμCT after chronic compression were consistent with the changes detected by immunofluorescence staining. The 3D morphological measurements revealed significant reductions of neurovascular parameters in the thoracic spinal cord after 1 month of compression and became even worse after 6 months without relief of compression. In addition, the distinct 3D morphological twist and the decrease in branches of the central sulcal artery after chronic compression vividly displayed that these could be the potential triggers leading to blood flow reduction and neural deficits of the thoracic spinal cord. Our findings propose a novel methodology for the 3D analysis of neurovascular repair in chronic spinal cord compression, both qualitatively and quantitatively. The results indicated that compression simultaneously caused vascular dysfunction and neuronal network impairment, which should be acknowledged as concurrent events after chronic thoracic spinal cord injury. Combining neuroprotection with vasoprotection may provide promising therapeutic targets for chronic thoracic spinal cord compression.