Central Nervous System Ischemia Research Articles

Using machine learning to predict neurologic injury in venovenous extracorporeal membrane oxygenation recipients: An ELSO Registry analysis

BackgroundVenovenous extracorporeal membrane oxygenation (VV-ECMO) is associated with acute brain injury (ABI), including central nervous system (CNS) ischemia (defined as ischemic stroke or hypoxic-ischemic brain injury [HIBI]) and intracranial hemorrhage (ICH). Data on prediction models for neurologic outcomes in VV-ECMO are limited. MethodsWe analyzed adult (age ≥18 years) VV-ECMO patients in the Extracorporeal Life Support Organization (ELSO) Registry (2009-2021) from 676 centers. ABI was defined as CNS ischemia, ICH, brain death, and seizures. Data on 67 variables were extracted, including clinical characteristics and pre-ECMO/on-ECMO variables. Random forest, CatBoost, LightGBM, and XGBoost machine learning (ML) algorithms (10-fold leave-one-out cross-validation) were used to predict ABI. Feature importance scores were used to pinpoint the most important variables for predicting ABI. ResultsOf 37,473 VV-ECMO patients (median age, 48.1 years; 63% male), 2644 (7.1%) experienced ABI, including 610 (2%) with CNS ischemia and 1591 (4%) with ICH. The areas under the receiver operating characteristic curve for predicting ABI, CNS ischemia, and ICH were 0.70, 0.68, and 0.70, respectively. The accuracy, positive predictive value, and negative predictive value for ABI were 85%, 19%, and 95%, respectively. ML identified higher center volume, pre-ECMO cardiac arrest, higher ECMO pump flow, and elevated on-ECMO serum lactate level as the most important risk factors for ABI and its subtypes. ConclusionsThis is the largest study of VV-ECMO patients to use ML to predict ABI reported to date. Performance was suboptimal, likely due to lack of standardization of neuromonitoring/imaging protocols and data granularity in the ELSO Registry. Standardized neurologic monitoring and imaging are needed across ELSO centers to detect the true prevalence of ABI.

Acute Brain Injury Risk Prediction Models in Venoarterial Extracorporeal Membrane Oxygenation Patients with Tree-Based Machine Learning: An ELSO Registry Analysis

ObjectiveWe aimed to determine if machine learning (ML) can predict acute brain injury (ABI) and identify modifiable risk factors for ABI in venoarterial extracorporeal membrane oxygenation (VA-ECMO) patients. MethodsWe included adults (≥18 years) receiving VA-ECMO or extracorporeal cardiopulmonary resuscitation (ECPR) in the Extracorporeal Life Support Organization Registry (2009-2021). Our primary outcome was ABI: central nervous system (CNS) ischemia, intracranial hemorrhage (ICH), brain death, and seizures. We utilized Random Forest, CatBoost, LightGBM and XGBoost ML algorithms (10-fold leave-one-out cross-validation) to predict and identify features most important for ABI. We extracted 65 total features: demographics, pre-ECMO/on-ECMO laboratory values, and pre-ECMO/on-ECMO settings. ResultsOf 35,855 VA-ECMO (non-ECPR) patients (median age=57.8 years, 66%=male), 7.7% (n=2,769) experienced ABI. In VA-ECMO (non-ECPR), the area under the receiver-operator characteristics curves (AUC-ROC) to predict ABI, CNS ischemia, and ICH was 0.67, 0.67, and 0.62, respectively. The true positive, true negative, false positive, false negative, positive, and negative predictive values were 33%, 88%, 12%, 67%, 18%, and 94%, respectively for ABI. Longer ECMO duration, higher 24h ECMO pump flow, and higher on-ECMO PaO2 were associated with ABI. Of 10,775 ECPR patients (median age=57.1 years, 68%=male), 16.5% (n=1,787) experienced ABI. The AUC-ROC for ABI, CNS ischemia, and ICH was 0.72, 0.73, and 0.69, respectively. Longer ECMO duration, older age, and higher 24h ECMO pump flow were associated with ABI. ConclusionsIn the largest study predicting neurological complications with ML in ECMO, longer ECMO duration and higher 24h pump flow were associated with ABI in non-ECPR and ECPR VA-ECMO.

Thrombolysis treatment and multi- disciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options

<p>The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo&shy;gi&shy;cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.</p>. <p>We reviewed CRAO patients&rsquo; data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo&shy;gical and cardiovascular findings compared to those in the thrombolysis project.&nbsp;</p>. <p>Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment.&nbsp;<br>2 pa&shy;tients had improved visual acuity, 2 pa&shy;tients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.</p>. <p>CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.</p>.

A Promising Application of Injectable Hydrogels in Nerve Repair and Regeneration for Ischemic Stroke.

Ischemic stroke, a condition that often leads to severe nerve damage, induces complex pathological and physiological changes in nerve tissue. The mature central nervous system (CNS) lacks intrinsic regenerative capacity, resulting in a poor prognosis and long-term neurological impairments. There is no available therapy that can fully restore CNS functionality. However, the utilization of injectable hydrogels has emerged as a promising strategy for nerve repair and regeneration. Injectable hydrogels possess exceptional properties, such as biocompatibility, tunable mechanical properties, and the ability to provide a supportive environment for cell growth and tissue regeneration. Recently, various hydrogel-based tissue engineering approaches, including cell encapsulation, controlled release of therapeutic factors, and incorporation of bioactive molecules, have demonstrated great potential in the treatment of CNS injuries caused by ischemic stroke. This article aims to provide a comprehensive review of the application and development of injectable hydrogels for the treatment of ischemic stroke-induced CNS injuries, shedding light on their therapeutic prospects, challenges, recent advancements, and future directions. Additionally, it will discuss the underlying mechanisms involved in hydrogel-mediated nerve repair and regeneration, as well as the need for further preclinical and clinical studies to validate their efficacy and safety.

Long-Term Follow-up of a Randomized Controlled Trial on Accelerated Radiation Therapy Versus Standard Fractionated Radiation Therapy for Early Glottic Cancer (JCOG0701A3)

We previously reported the primary results of JCOG0701, a randomized, multicenter, phase III, non-inferiority trial comparing accelerated fractionation (Ax) to standard fractionation (SF) for early glottic cancer (GC). In the primary results, although the similar efficacy of 3-year PFS and toxicity of Ax compared with SF was observed, the non-inferiority of Ax was not confirmed statistically. To evaluate the long-term follow-up results of JCOG0701, we conducted JCOG0701A3 as an ancillary study of JCOG0701. In JCOG0701, 370 patients were randomly assigned to receive SF of 66-70 Gy (33-35 fractions) (n=184) or Ax of 60-64.8 Gy (25-27 fractions) (n=186). The data cutoff date for this analysis was in June 2020. Overall survival, progression-free survival, and late adverse events including central nervous system ischemia (CNSI) were analyzed. With median follow-up period of 7.1 years (range: 0.1-12.4), PFS of the SF and Ax arms were 76.2% and 78.2% at 5 years and 72.7% and 74.8% at 7 years (p=0.44). OS of SF and Ax arms were 92.7% and 89.6% at 5 years and 90.8% and 86.5% at 7 years (p=0.92). Among 366 patients with a protocol treatment, the cumulative incidence of late adverse events of SF and Ax arms were 11.9% and 7.4% at 8 years (HR: 0.53, 95% CI: 0.28-1.01, p=0.06). CNSI of Grade 2 or higher was observed in 4.1% for SF arms and 1.1% for Ax arm (p=0.098). After a long-term follow-up Ax showed comparable efficacy to SF and a tendency for better safety. Ax may be suitable for early GC because of its convenience in minimizing treatment time, cost, and labor.

Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.

The effects of Bone Morphogenetic Protein 4 on adult neural stem cell proliferation, differentiation and survival in an in vitro model of ischemic stroke

The subventricular zone (SVZ) of the lateral ventricles represents a main region where neural stem cells (NSCs) of the mature central nervous system (CNS) reside. Bone Morphogenetic Proteins (BMPs) are the largest subclass of the transforming growth factor-β (TGF-β) superfamily of ligands. BMP4 is one such member and plays important roles in adult NSC differentiation. However, the exact effects of BMP4 on SVZ adult NSCs in CNS ischemia are still unknown. Using oxygen and glucose deprivation (OGD) as an in vitro model of ischemia, we examined the behavior of adult NSCs. We observed that anoxia resulted in reduced viability of adult NSCs, and that BMP4 treatment clearly rescued apoptotic cell death following anoxia. Furthermore, BMP4 treatment exhibited a strong inhibitory effect on cellular proliferation of the adult NSCs in normoxic conditions. Moreover, such inhibitory effects of BMP4 treatment were also found in OGD conditions, despite the enhanced cellular proliferation of the adult NSCs that was observed under such ischemic conditions. Increased neuronal and astroglial commitment of adult NSCs were found in the OGD conditions, whereas a reduction in differentiated neurons and an increase in differentiated astrocytes were observed following BMP4 treatment. The present data indicate that BMP4 modulates proliferation and differentiation of SVZ-derived adult NSCs and promotes cell survival in the in vitro model of ischemic stroke.

Polyarteritis Nodosa: State of the art.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that preferentially affects medium-sized vessels. The idiopathic form has become rare. Its treatment relies on corticosteroid therapy and is combined with cyclophosphamide infusions for severe forms. Secondary PANs were mainly associated with hepatitis B virus infection; they were treated with plasma exchange and antivirals in combination with short-term corticosteroid therapy. Other secondary forms of PAN are now becoming more common, such as those due to blood disorders. More recently, a monogenic form linked to adenosine deaminase-2 mutations has been identified. It requires treatment with TNF inhibitors to decrease the occurrence of ischemic central nervous system complications, which make it serious. Once remission is obtained, relapses are typically rare during PAN and affect 28% of idiopathic PANs, within an average of 26 months from the diagnosis. The prognosis has improved considerably, with 5- and 10-year survival rates of 83% and 74%.

Stem Cell Therapies for Restorative Treatments of Central Nervous System Ischemia-Reperfusion Injury.

Ischemic damage to the central nervous system (CNS) is a catastrophic postoperative complication of aortic occlusion subsequent to cardiovascular surgery that can cause brain impairment and sometimes even paraplegia. Over recent years, numerous studies have investigated techniques for protecting and revascularizing the nervous system during intraoperative ischemia; however, owing to a lack of knowledge of the physiological distinctions between the brain and spinal cord, as well as the limited availability of testing techniques and treatments for ischemia-reperfusion injury, the cause of brain and spinal cord ischemia-reperfusion injury remains poorly understood, and no adequate response steps are currently available in the clinic. Given the limited ability of the CNS to repair itself, it is of great clinical value to make full use of the proliferative and differentiation potential of stem cells to repair nerves in degenerated and necrotic regions by stem cell transplantation or mobilization, thereby introducing a novel concept for the treatment of severe CNS ischemia-reperfusion injury. This review summarizes the most recent advances in stem cell therapy for ischemia-reperfusion injury in the brain and spinal cord, aiming to advance basic research and the clinical use of stem cell therapy as a promising treatment for this condition.

Diversity of Reactive Astrogliosis in CNS Pathology: Heterogeneity or Plasticity?

Astrocytes are essential for the development and homeostatic maintenance of the central nervous system (CNS). They are also critical players in the CNS injury response during which they undergo a process referred to as “reactive astrogliosis.” Diversity in astrocyte morphology and gene expression, as revealed by transcriptional analysis, is well-recognized and has been reported in several CNS pathologies, including ischemic stroke, CNS demyelination, and traumatic injury. This diversity appears unique to the specific pathology, with significant variance across temporal, topographical, age, and sex-specific variables. Despite this, there is limited functional data corroborating this diversity. Furthermore, as reactive astrocytes display significant environmental-dependent plasticity and fate-mapping data on astrocyte subsets in the adult CNS is limited, it remains unclear whether this diversity represents heterogeneity or plasticity. As astrocytes are important for neuronal survival and CNS function post-injury, establishing to what extent this diversity reflects distinct established heterogeneous astrocyte subpopulations vs. environmentally dependent plasticity within established astrocyte subsets will be critical for guiding therapeutic development. To that end, we review the current state of knowledge on astrocyte diversity in the context of three representative CNS pathologies: ischemic stroke, demyelination, and traumatic injury, with the goal of identifying key limitations in our current knowledge and suggesting future areas of research needed to address them. We suggest that the majority of identified astrocyte diversity in CNS pathologies to date represents plasticity in response to dynamically changing post-injury environments as opposed to heterogeneity, an important consideration for the understanding of disease pathogenesis and the development of therapeutic interventions.

Epidemiology of Balance Disorders in Primary Care

Background and objectiveIn our country, there are no series of patients that have described the incidence of the different diseases which cause balance disorders (BD) in primary care. The objective of this study is to calculate the incidence of each disease to propose specific training measures. Materials and methodProspective cross-sectional study. Patient data of five primary care physicians in five different primary care centres in our hospital area were collected. All patients who attended consultations for any type of vertigo, imbalance or dizziness over one year were recruited as well as the main reason for consultation. Using a diagnostic-therapeutic algorithm, patients were diagnosed and treated in primary care or referred for study in hospital care. ResultsThe population studied was 7896 people. An annual incidence of BD of 2.2% was detected. Of the cases, 56.1% could be diagnosed and treated in primary care. Of the patients, 53.8% were diagnosed with some type of positional vertigo; the next three most frequent diagnoses were vestibular migraine, central nervous system ischaemia and medication side effects. These four groups accounted for 87.9% of the population. ConclusionsThe incidence of BD in primary care requires an approach that includes training in the diagnosis and treatment of benign paroxysmal positional vertigo, headache, cardiovascular risk factors and pharmacology. It is not necessary to prescribe vestibular suppressants in most patients.

Re-initiation of anticoagulation after central nervous system hemorrhage during treatment with direct oral anticoagulants: a single hospital cohort study.

Central nervous system (CNS) hemorrhage is a serious complication related to direct oral anticoagulant (DOAC) therapy. Current recommendations about re-initiation of anticoagulation treatment are limited to expert opinions. For this purpose, we analyzed the data of all consecutive DOAC patients with CNS hemorrhage, in whom DOACs were reinitiated. Over a 6-year period (2012-2018), all consecutive patients with CNS hemorrhage (subdural, subarachnoid, intracerebral, spinal), while receiving DOACs, were included in this observational single-center cohort study. DOAC therapy was reinitiated only in patients with well-controlled arterial hypertension and diabetes, as well as exclusion of vascular malformations and cerebral amyloid angiopathy. The composite primary endpoint comprised of recurrent CNS hemorrhage, ischemic stroke, and mortality; secondary endpoints were separate aforementioned outcomes. Of the 54 patients included, 18 died within a month of CNS hemorrhage. The average observational time was 590days. DOACs were reinitiated in 13/36 patients (36%); of these patients, three died: none due to ischemic stroke or recurrent CNS bleeding. In 23 patients, anticoagulation was not reinitiated; of these patients, 10 died: three from recurrent CNS hemorrhage, one due to ischemic stroke, and six from causes unrelated to stroke. In carefully selected patients, re-initiation of DOAC therapy did not increase the rate of both endpoints. Recommendations for DOAC re-initiation, which include hypertension and diabetes control, as well as treated vascular malformations, and excluded cerebral amyloid angiopathy, appear to be valid in clinical practice.

Human endothelial colony-forming cells in regenerative therapy: A systematic review of controlled preclinical animal studies.

Endothelial colony‐forming cells (ECFCs) hold significant promise as candidates for regenerative therapy of vascular injury. Existing studies remain largely preclinical and exhibit marked design heterogeneity. A systematic review of controlled preclinical trials of human ECFCs is needed to guide future study design and to accelerate clinical translation. A systematic search of Medline and EMBASE on 1 April 2019 returned 3131 unique entries of which 66 fulfilled the inclusion criteria. Most studies used ECFCs derived from umbilical cord or adult peripheral blood. Studies used genetically modified immunodeficient mice (n = 52) and/or rats (n = 16). ECFC phenotypes were inconsistently characterized. While >90% of studies used CD31+ and CD45−, CD14− was demonstrated in 73% of studies, CD146+ in 42%, and CD10+ in 35%. Most disease models invoked ischemia. Peripheral vascular ischemia (n = 29), central nervous system ischemia (n = 14), connective tissue injury (n = 10), and cardiovascular ischemia and reperfusion injury (n = 7) were studied most commonly. Studies showed predominantly positive results; only 13 studies reported ≥1 outcome with null results, three reported only null results, and one reported harm. Quality assessment with SYRCLE revealed potential sources of bias in most studies. Preclinical ECFC studies are associated with benefit across several ischemic conditions in animal models, although combining results is limited by marked heterogeneity in study design. In particular, characterization of ECFCs varied and aspects of reporting introduced risk of bias in most studies. More studies with greater focus on standardized cell characterization and consistency of the disease model are needed.

Epidemiología de los trastornos del equilibrio en atención primaria

Background and objectiveIn our country, there are no series of patients that have described the incidence of the different diseases which cause balance disorders (BD) in primary care. The objective of this study is to calculate the incidence of each disease to propose specific training measures. Materials and methodProspective cross-sectional study. Patient data of five primary care physicians in five different primary care centres in our hospital area were collected. All patients who attended consultations for any type of vertigo, imbalance or dizziness over one year as the main reason for consultation were recruited. Using a diagnostic-therapeutic algorithm, patients were diagnosed and treated in primary care or referred for study in hospital care. ResultsThe population studied was 7,896 people. An annual incidence of BD of 2.2% was detected. Of the cases, 56.1% could be diagnosed and treated in primary care. Of the patients, 53.8% were diagnosed with some type of positional vertigo; the next three most frequent diagnoses were vestibular migraine, central nervous system ischaemia and medication side effects. These four groups accounted for 87.9% of the population. ConclusionsThe incidence of BD in primary care requires an approach that includes training in the diagnosis and treatment of benign paroxysmal positional vertigo, headache, cardiovascular risk factors and pharmacology. It is not necessary to prescribe vestibular suppressants in most patients.

Prevalence of atherosclerotic stenosis of the carotid and cerebral arteries in patients with stable or unstable coronary artery disease.

Carotid artery atherosclerosis is a recognized predictor of cardiovascular events. The coexistence of coronary atherosclerosis and cerebrovascular disease is associated with unfavorable clinical outcomes. The aim of this study was to determine the prevalence of hemodynamically and clinically significant carotid and / or cerebral artery stenosis in patients with stable and unstable coronary artery disease (CAD). Cardiac and neurological examinations together with coronary angiography and carotid ultrasound were performed in 241 patients, and transcranial Doppler imaging of cerebral arteries in 114. The prevalence of hemodynamically significant internal carotid artery (ICA) stenosis, intracranial artery stenosis, and clinical signs of central nervous system ischemia were compared between patients with stable and unstable CAD. There was no significant difference in the prevalence of ICA stenosis (15.3% vs 19%) and intracranial artery stenosis (18% vs 16%) between patients with stable and unstable CAD. Risk factors for cerebral artery stenosis included ICA stenosis (odds ratio [OR], 13.21; 95% CI, 5.93-41.89) and advanced CAD (OR, 2.38; 95% CI, 1.13-4.09), and for ischemic events within the central nervous system, ICA stenosis (OR, 1.74; 95% CI, 1.01-3.16) and intracranial artery stenosis (OR, 3.01; 95% CI, 1.66-5.57). No differences in the prevalence of atherosclerosis of the carotid and cerebral arteries were found between patients with stable and unstable CAD in this study. Advanced CAD is one of the risk factors for hemodynamically significant cerebral artery stenosis.

Application of a new blood flow regulator in aortic endovascular therapy

BackgroundEndovascular repair involving branches of the aorta is still difficult in clinical treatment. A new type of blood flow regulator has been used in thoracic endovascular aortic repair/endovascular aortic repair in our centre, and the effects were followed and analysed.MethodsFrom March 2014 to January 2015, 14 patients with Stanford type B aortic dissection or penetrating ulcers and aortic arch pseudoaneurysms were consecutively enrolled. All patients were evaluated and underwent endovascular repair. The average age of these patients was 59 ± 14 years (34–76 years old, median 62 years), and there were 12 males and 2 females. The blood flow regulator was a self-expanding membrane-supported artificial blood vessel. The film was made from polyester that was formed into a mesh 1 mm2 in size. The metal stent used was made of nickel-titanium alloy.ResultsThe success rate for the technique was 100%. All patients underwent postoperative aortic CTA and had type III endoleak. There were no deaths and no instances of stroke, transient ischemic attack (TIA), hemiplegia, paraplegia or other central nervous system complications, and there were no left upper limb ischaemia symptoms in the group. The average follow-up time was 14.7 ± 3.6 months. One patient died of sudden death 4 months after the operation. One patient died due to abdominal aortic aneurysm rupture, and the other 12 patients survived. The survival rate was 86%. The blood flow regulator covered a total of 19 branch vessels (the intercostal artery was not counted), of which 18 experienced smooth blood flow. One patient continued to have a type III endoleak after the operation, and the endoleak disappeared after endovascular repair.ConclusionsThis clinical case series of 14 patients with percutaneous transluminal stents indicates that the blood flow regulator is safe and feasible in TEVAR surgery, providing a promising new technology.

Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke

Angiogenesis is a key restorative process following stroke but has also been linked to increased vascular permeability and blood brain barrier (BBB) disruption. Previous pre-clinical approaches primarily focused on the administration of vascular endothelial growth factor (VEGF) to promote vascular repair after stroke. Although shown to improve angiogenesis and functional recovery from stroke, VEGF increased the risk of blood brain barrier disruption and bleedings to such an extent that its clinical use is contraindicated. As an alternative strategy, antibodies against the neurite growth inhibitory factor Nogo-A have recently been shown to enhance vascular regeneration in the ischemic central nervous system (CNS); however, their effect on vascular permeability is unknown. Here, we demonstrate that antibody-mediated Nogo-A neutralization following stroke has strong pro-angiogenic effects but does not increase vascular permeability as opposed to VEGF. Moreover, VEGF-induced vascular permeability was partially prevented when VEGF was co-administered with anti-Nogo-A antibodies. This study may provide a novel therapeutic strategy for vascular repair and maturation in the ischemic brain.

Outcome of Initiating Hydroxyurea in Infancy for Patients with Sickle Cell Disease 2011-2018

IntroductionApproximately 2000 babies are born with sickle cell disease annually in the US. Children with severe forms of sickle cell disease (SCD), such as Hemoglobin SS and Hemoglobin S beta 0 thalassemia (Sbeta0), are at risk for severe anemia, vasoocclusive pain crisis, acute chest syndrome, splenic sequestration, central nervous system ischemia, and shortened life expectancy. The drug Hydroxyurea (HU) increases Hgb F, is effective in ameliorating many sickle cell symptoms, and improves survival. Safety and efficacy of HU in children and infants have been demonstrated.MethodsFollowing publication of the BABY HUG trial results in 2011, the Comprehensive Pediatric Sickle Cell Program of Northern Virginia implemented HU initiation for all infants with Hgb SS or Hgb Sbeta0. HU was prescribed at age 6-7 months for 2 patients and at 9-12 months of age for 22 patients. HU dosage was diligently adjusted at clinic visits to maximize Hgb F. An IRB-approved prospective, longitudinal database was launched to follow each patient's clinical course and outcome in 6-month increments. Data are reported for children born after January 2011 who were started on HU by 12 months of age, followed on HU therapy continuously in this clinic, and were at least 2 years of age by June 2018.ResultsAll 24 children in the analysis have Hgb SS. Sixteen children have been followed for 3 years or more, 11 children have been followed for 4 years or more, 7 children have been followed for 5 years or more, 4 children have been followed for 6 years or more, and 3 children have been followed for 7 years. Average Hgb at 6 months of age was 9.5 g/dL, and ranged between 9.5 and 10.7 g/dL for age 1-7. Average Hgb F was 34.1% at 6 months of age and dipped to 29.1% at 1 year of age, but was maintained above 30% from age 1.5 - 3 years and at 27.8% - 30.5% for age 3.5 - 7 years. For a total of 92 person-years, there were 27 hospitalizations, all within the first 3 years of life. 20/27 (74%) hospitalizations were for fever, pneumonia without hypoxia or need for transfusion, or other infections, 5/27 (19%) were for splenic sequestration, and only 1/27 (4%) hospitalization was for pain that occurred before HU initiation. ED visits totaled 68, 53/68 (78%) were for fever and 47/68 (69%) occurred in the first 3 years of life. Only 2/68 (3%) ED visits were attributed to dactylitis/pain, occurring prior to HU initiation. ED visits after age 3 were all for fevers. The most common complication specific to sickle cell disease was splenic sequestration, which is not preventable by HU. All 4 transfusions given were for splenic sequestration.ConclusionContinuous tracking in a single center observational study demonstrated that continuous HU therapy starting in infancy maintained Hgb and Hgb F at or above pre-HU levels into childhood, is associated with no hospitalizations after age 3 and no ED visits for pain after HU initiation by age 1. No acute chest syndrome requiring oxygen or transfusion, no abnormal or conditional TCD, and no overt strokes occurred in this cohort. Implementation of HU for children with sickle cell disease starting in infancy is feasible in the community and is effective in maintaining high fetal hemoglobin and preventing disease complications. DisclosuresNo relevant conflicts of interest to declare.

A Glimpse into Uveitis in the Aging Eye: Pathophysiology, Clinical Presentation and Treatment Considerations.

Uveitis describes a group of inflammatory conditions of the eye that have various underlying causes and clinical presentations. Susceptibilities to uveitis in the elderly may be attributed to age-related risk factors such as immunosenescence, increased immunological inflammatory mediators, and autoimmunity. Overall, anterior uveitis is more common than posterior and panuveitis in the general population and also in the elderly. Some causes of uveitis in the elderly are herpes simplex virus, ocular ischemic syndrome, sarcoidosis, and central nervous system lymphoma, and these will be discussed in detail herein. Eye care professionals need to consider the wide differential for uveitis, obtain the appropriate history, conduct a detailed clinical examination, and tailor management to the clinical presentation and underlying cause of disease. The challenges of polypharmacy and nonadherence in the elderly impact patient outcomes and must be taken into consideration when considering treatment.

Comorbidity of chronic obstructive pulmonary disease and&#x0D; ischemic stroke.

This review summarizes the literature on the problem of comorbidity of chronic obstructive pulmonary disease (COPD) and ischemic stroke (IS). The basic mechanisms of interrelation of these diseases. According to various sources the prevalence of IS in patients with COPD by 20% higher than in the general population. COPD and IS have common risk factors, the main of which is considered the age and smoking. Such manifestations of COPD such as chronic systemic inflammation (HSV), oxidative stress, accelerated atherogenesis, increased thrombotic risk events, arterial hypoxemia and hypercapnia may also influence the frequency of occurrence of IS. The importance given to the role in the development of COPD, certain subtypes of IS. Thus, HSV increases the intensity of the processes of atherogenesis and causes destabilization of atherosclerotic plaques, which increases the risk of developing atherothrombotic subtype of IS. COPD is a major factor of vascular comorbidity, promotes hemodynamic and cardioembolic subtype IS. It is therefore evident that a more frequent occurrence of ischemic central nervous system damage in patients with COPD compared to the general population is the result of the combined effect on cerebral blood flow and brain morphological structure of multiple pathogenic factors associated with systemic manifestations of the disease. Therapy options for comorbid COPD and IS flow needs to be improved. Thus, further study of comorbidity of COPD and AI mechanisms, understanding of the role and place of the respiratory and cerebrovascular syntropy, in the development of these diseases opens up prospects for the implementation of modern strategies of rational therapy.