Boosting Mitochondrial Biogenesis Diminishes Foam Cell Formation in the Post-Stroke Brain.

Following ischemic stroke, the degradation of myelin and other cellular membranes surpasses the lipid-processing capabilities of resident microglia and infiltrating macrophages. This imbalance leads to foam cell formation in the infarct and areas of secondary neurodegeneration, instigating sustained inflammation and furthering neurological damage. Given that mitochondria are the primary sites of fatty acid metabolism, augmenting mitochondrial biogenesis (MB) may enhance lipid processing, curtailing foam cell formation and post-stroke chronic inflammation. Previous studies have shown that the pharmacological activation of the ß2-adrenergic receptor (ß2-AR) stimulates MB. Consequently, our study sought to discern the effects of intensified ß2-AR signaling on MB, the processing of brain lipid debris, and neurological outcome using a mouse stroke model. To achieve this goal, aged mice were treated with formoterol, a long-acting ß2-AR agonist, daily for two and eight weeks following stroke. Formoterol increased MB in the infarct region, modified fatty acid metabolism, and reduced foam cell formation. However, it did not reduce markers of post-stroke neurodegeneration or improve recovery. Although our findings indicate that enhancing MB in myeloid cells can aid in the processing of brain lipid debris after stroke, it is important to note that boosting MB alone may not be sufficient to significantly impact stroke recovery.

L-SeqSleepNet: Whole-cycle Long Sequence Modeling for Automatic Sleep Staging.

Human sleep is cyclical with a period of approximately 90 minutes, implying long temporal dependency in the sleep data. Yet, exploring this long-term dependency when developing sleep staging models has remained untouched. In this work, we show that while encoding the logic of a whole sleep cycle is crucial to improve sleep staging performance, the sequential modelling approach in existing state-of-the-art deep learning models are inefficient for that purpose. We thus introduce a method for efficient long sequence modelling and propose a new deep learning model, L-SeqSleepNet, which takes into account whole-cycle sleep information for sleep staging. Evaluating L-SeqSleepNet on four distinct databases of various sizes, we demonstrate state-of-the-art performance obtained by the model over three different EEG setups, including scalp EEG in conventional Polysomnography (PSG), in-ear EEG, and around-the-ear EEG (cEEGrid), even with a single EEG channel input. Our analyses also show that L-SeqSleepNet is able to alleviate the predominance of N2 sleep (the major class in terms of classification) to bring down errors in other sleep stages. Moreover the network becomes much more robust, meaning that for all subjects where the baseline method had exceptionally poor performance, their performance are improved significantly. Finally, the computation time only grows at a sub-linear rate when the sequence length increases.

LASER THERAPY OF RETINAL TEARS.

AIM: To report the clinical results of treatment of patients with retinal tears or holes, including rhegmatogenous retinal detachment, who were treated primarily with laser retinopexy. MATERIAL AND METHODS: The effect and results of the therapy of patients with one or more retinal tears who underwent therapy with the green laser IQ 532 IRIDEX between December 2019 and August 2022 at our center with a follow-up observation period of at least 3 months were retrospectively evaluated. RESULTS: A total of 14 eyes of 14 patients were treated by this method during the monitored period. All the tears found were primarily successfully repaired. The overall success rate of prophylaxis of rhegmatogenous retinal detachment was 93% in our cohort. In one patient, subsequent pars plana vitrectomy was required due to the progression of retinal detachment from another biomicroscopically inaccessible hole, which was part of lattice degeneration in the peripheral part of the retina. This pathology was only verified during intraocular surgery. Postoperatively, the retina was attached with a very good anatomical and functional effect. The other patients did not require any adjuvant therapy. Visual functions improved or remained stable in all patients in the cohort. The follow-up observation period ranged from 3 to 36 months. CONCLUSION: Laser retinopexy is a sparing, safe and effective method of retinal tear therapy. From our clinical experience, the technique is also applicable in the case of partial vitreous hemorrhage or incipient rhegmatogenous detachment. We did not record any complications of perioperative or postoperative treatment among our patients.

Targeting foam cell formation to improve recovery from ischemic stroke.

Inflammation is a crucial part of the healing process after an ischemic stroke and is required to restore tissue homeostasis. However, the inflammatory response to stroke also worsens neurodegeneration and creates a tissue environment that is unfavorable to regeneration for several months, thereby postponing recovery. In animal models, inflammation can also contribute to the development of delayed cognitive deficits. Myeloid cells that take on a foamy appearance are one of the most prominent immune cell types within chronic stroke infarcts. Emerging evidence indicates that they form as a result of mechanisms of myelin lipid clearance becoming overwhelmed, and that they are a key driver of the chronic inflammatory response to stroke. Therefore, targeting lipid accumulation in foam cells may be a promising strategy for improving recovery. The aim of this review is to provide an overview of current knowledge regarding inflammation and foam cell formation in the brain in the weeks and months following ischemic stroke and identify targets that may be amenable to therapeutic intervention.

Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke.

The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naïve and sham mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid ß-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naïve controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. Spatial transcriptomics and RNA in situ hybridization localized these alterations to microglia within the area of axonal degeneration. These results indicate that chronic metabolic differences exist between stroked and control brains, including alterations in fatty acid metabolism and glycolysis within microglia in areas of degenerating white matter for at least 12 weeks after stroke.

CHELATION OF BAND KERATOPATHY IN LONG-TERM MONITORING.

AIM: To report the clinical results of chelation of band keratopathy in long-term follow-up. MATERIAL AND METHODS: The long-term results of 5 patients (5 eyes) with symptomatic band keratopathy with a follow-up period of at least 6 months, in whom 2% EDTA was chelated on the affected eye in the study period from April 2018 to March 2021, were retrospectively evaluated. The follow-up period was 9-37 months. RESULTS: In all patients, there was a significant improvement in the local findings and an increase in the transparency of the cornea. The effect of therapy was verified on a color photograph of the anterior segment and on AS-OCT by the disappearance of subepithelial hyperreflective foci and accompanying optical shadows. Postoperatively, this enabled a more detailed visualization of the deeper layers of the cornea and other structures of the anterior segment. In a patient with the potential to improve vision, it was also possible to significantly improve visual functions. In the other three patients with pain in the affected eye, the pain subsided, and they also benefited cosmetically from the operation. CONCLUSION: Based on our experience and previously published reports, EDTA corneal chelation is able to causally resolve the pathology and improve vision in eyes with visual potential. At the same time, it reduces discomfort and has an analgesic effect in long-term irritated eyes. The operation is also suitable for amaurotic, cosmetically unsightly bulbs, as a successful intervention preserving the eye and improving the appearance of such eyes leads to satisfaction and a subjective increase in the quality of life of the patients.

INCIDENCE OF PSEUDOEXFOLIATION SYNDROME AND GLAUCOMA IN A SET OF MORE THAN 14,000 EYES OF PATIENTS OPERATED FOR A CATARACT.

PURPOSE: Evaluation of the incidence of pseudoexfoliation (PEX) syndrome and glaucoma in cataract patients operated at our Clinic, with an analysis of possible complications. METHODOLOGY: Retrospective evaluation of medical records of PEX syndrome patients who have undergone cataract surgery at the Gemini Eye Clinic Ostrava-Hrusov was undertaken. The study period was from November 2016 to April 2021. The evaluated parameters were the incidence of PEX syndrome, age and gender of patients, intraocular pressure (IOP) before the surgery, pre-existing therapy of previously diagnosed secondary glaucoma and the occurrence of perioperative complications. RESULTS: In the study period of 4.5 years, out of the total number of 14 167 operated eyes with cataracts there were 852 eyes of 689 patients with PEX syndrome diagnosed at our Clinic, i.e. 6.0 %. The mean age was 76.9 years, the median 77 years, range 54-100 years. The observed pathology was more common in women at a ratio of 1.84: 1 (552: 300). Elevation of IOP above 21 mmHg was recorded in 118 eyes, in 14 of them IOP reached values over 30 mmHg. Diagnosed and long-term treated secondary glaucoma was confirmed by 153 patients (204 eyes), out of which 22 eyes have undergone antiglaucoma laser (19 eyes) and / or surgery (5 eyes) in the anamnesis. Perioperatively, we recorded the following pathological findings accompanying the occurrence of PEX syndrome in 231 eyes. Most often it was poor artificial mydriasis (189 eyes), then subluxation of the lens (31 eyes) or zonular fragility (17 eyes). To reduce the risk of perioperative and postoperative complications, implantation of a capsular tension ring was indicated in 20 eyes. Complications during the procedure occurred in 11 eyes, of which 8 eyes were diagnosed with advanced cataract. CONCLUSION: PEX syndrome and glaucoma are relatively common diseases that can complicate the lives of patients and eye surgeons. The incidence of PEX syndrome in our cataract patients was 6 %. Proper diagnosis of this disease is important not only for the possible occurrence of numerous complications during and after cataract surgery, but also for the possible presence of secondary glaucoma. It also serves to detect possible involvement of the contralateral eye. In addition, due to the involvement of practically all tissues in the body, the patient is endangered by numerous, especially vascular comorbidities. For these reasons, we find it appropriate that these patients are observed by other healthcare specialists. In our experience, early indication of cataract surgery is important to achieve a lower degree of zonular fragility and a softer lens core. In addition, lower levels of proinflammatory pseudoexfoliation material occur in the anterior segment of the eye in the early stages, which may have a beneficial effect on the postoperative healing.

Implementing Patient-Reported Outcome Measures in Inpatient Rehabilitation: Challenges and Solutions.

A project with the goal of implementing electronic health record (EHR)-based patient-reported outcome measures (PROMs) into a large inpatient spinal cord injury (SCI) rehabilitation program took twice as long as expected. This report details the lessons learned from the barriers, successes, and unexpected issues that arose during this prolonged, but now successful, project. The goals of this implementation project were to (1) identify barriers and supports to the use of PROMs; (2) develop an implementation strategy to incorporate the use of PROMs into inpatient rehabilitation; and (3) implement the strategy and evaluate its effects on team communication. In brief, we conducted an initial pilot phase outside of the EHR and used our findings to guide procedural and EHR incorporation during a demonstration phase. We encountered multiple barriers. Procedural issues were significant; although grant funding covered the cost of writing the code for integration of the PROMs into the EHR, our institution's competing priorities slowed progress. Institutional inertia was reflected in the reluctance of some clinical staff members to assume new duties that would take away from direct patient care responsibilities. Therefore, we needed to obtain additional staffing. Detailed planning upfront, guided by changes when necessary; cooperation and interaction with our institution's Information Systems department; and identification of key players and Implementation Champions proved essential to our success. We now have an up-and-running system and are sharing our experience, observations, and recommendations to assist other health care organizations incorporate PROMs into their EHRs.

Repeated Administration of 2-Hydroxypropyl-ß-Cyclodextrin (HPßCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke.

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPßCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPßCD 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HPßCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPßCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPßCD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HPßCD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HPßCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents poststroke cognitive decline.SIGNIFICANCE STATEMENT Dementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for poststroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HPßCD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HPßCD for the prevention of poststroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.

Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery.

The aim of this study was to test whether poststroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle-treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke-induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks after stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31-treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31-treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75NTR for preserving neuronal health and function during stroke recovery. SIGNIFICANCE STATEMENT: The findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer's disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia.

BACKGROUND: Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1-7 (Ang-(1-7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1-7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model. METHODS: VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1-7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05. RESULTS: Treatment with Ang-(1-7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain. CONCLUSIONS: These data show that treatment with Ang-(1-7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.

Integrating Spinal Cord Injury - Quality of Life instruments into rehabilitation: Implementation science to guide adoption of patient-reported outcome measures.

Context/objective: This study describes a development strategy for integrating the Spinal Cord Injury - Quality of Life (SCI-QOL) item banks into inpatient spinal cord injury (SCI) rehabilitation and recommendations for protocol implementation.Design: We adopted an implementation science approach to develop a strategy for adapting and contextualizing SCI-QOL use during SCI rehabilitation. We conducted focus groups and stakeholder meetings with clinical assessment champions to (1) identify barriers and supports to SCI-QOL adoption; (2) reduce barriers and emphasize supports; (3) evaluate and select relevant SCI-QOL domains and item banks; (4) develop administration and reporting guidelines; and (5) identify hospital roles to alert with SCI-QOL results.Setting: A regional inpatient rehabilitation hospital. This study focuses on clinicians providing inpatient rehabilitation to patients with SCI.Participants: Fifty-nine clinicians, including physicians, speech language pathologists, occupational and physical therapists, nurses, and social workers providing care to SCI inpatients.Interventions: N/A.Outcome measures: N/A.Results: Clinicians identified the SCI-QOL domains that were most relevant to inpatient care; when SCI-QOL should be administered; what hospital roles were best suited for administering SCI-QOL; how results should be displayed in the electronic medical record; and which clinical roles needed notification of SCI-QOL results.Conclusions: Clinicians acknowledge the value of patient-reported outcome measures in inpatient SCI rehabilitation, but noted barriers to adoption. Engaging clinicians in the decision-making process for developing an implementation and administration protocol can inform strategies to overcome barriers and emphasize supports.

IgA natural antibodies are produced following T-cell independent B-cell activation following stroke.

Up to 30% of stroke patients experience cognitive decline within one year of their stroke. There are currently no FDA-approved drugs that can prevent post-stroke cognitive decline, in part due to a poor understanding of the mechanisms involved. We have previously demonstrated that a B-lymphocyte response to stroke, marked by IgA + cells, can cause delayed cognitive dysfunction in mice and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. The stimuli which trigger B-lymphocyte activation following stroke, and their target antigens, are still unknown. Therefore, to learn more about the mechanisms by which B-lymphocytes become activated following stroke we first characterized the temporal kinetics of the B-lymphocyte, T-lymphocyte, and plasma cell (PC) response to stroke in the brain by immunohistochemistry (IHC). We discovered that B-lymphocyte, T-lymphocyte, and plasma cell infiltration within the infarct progressively increases between 2 and 7 weeks after stroke. We then compared the B-lymphocyte response to stroke in WT, MHCII-/-, CD4-/-, and MyD88-/- mice to determine if B-lymphocytes mature into IgA + PCs through a T-lymphocyte and MyD88 dependent mechanism. Our data from a combination of IHC and flow cytometry indicate that following stroke, a population of IgA + PCs develops independently of CD4 + helper T-lymphocytes and MyD88 signaling. Subsequent sequencing of immunoglobulin genes of individual IgA + PCs present within the infarct identified a novel population of natural antibodies with few somatic mutations in complementarity-determining regions. These findings indicate that a population of IgA + PCs develops in the infarct following stroke by B-lymphocytes interacting with one or more thymus independent type 2 (TI-2) antigens, and that they produce IgA natural antibodies.

Rasch Analysis of Social Attitude Barriers and Facilitators to Participation for Individuals with Disabilities.

OBJECTIVES: To develop item banks of social attitude barriers and facilitators to participation and validate them with established instruments. DESIGN: We used the Rasch model to identify misfitting items and rating scale problems, calibrate items, and develop KeyForms and short forms. Correlations between the Social Attitude Barriers and Facilitators item banks with the Patient-Reported Outcomes Measurement Information System (PROMIS) Social Health domain and National Institutes of Health Toolbox Emotional Battery Social Relationships domain were computed to evaluate convergent and divergent validity. SETTING: Community-dwelling individuals traveled to 3 academic medical centers for testing. PARTICIPANTS: Participants (N=558) who had a primary impairment of stroke, spinal cord injury, or traumatic brain injury (mean age, 47.0±16.0y) completed 31 social attitude facilitator and 51 barrier items using a 5-point rating scale. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Item banks to measure social attitude barriers and facilitators for individuals with disabilities. RESULTS: After combining the "never" and "rarely" rating scale categories, 30 Facilitator items fit the Rasch model and demonstrated person reliability of 0.93. After collapsing the "never" and "rarely" rating scale categories, 45 Barrier items fit the Rasch model and demonstrated person reliability of 0.95. Ceiling and floor effects were negligible for both item banks. Facilitators and Barriers item banks were negatively correlated, and these banks were moderately correlated with PROMIS and Toolbox measures, providing evidence of convergent and divergent validity. CONCLUSIONS: Findings support the reliability and validity of the Social Attitude Facilitators and Barriers item banks. These item banks allow investigators and clinicians to measure perceptions of social attitudes, providing information that can guide individual interventions to reduce barriers and promote facilitators. Moderate correlations between the Social Attitude banks and PROMIS and Toolbox variables provide support for the measurement and theory of environmental influences on social health and participation.

Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.

Immunological mechanisms in poststroke dementia.

PURPOSE OF REVIEW: To review new evidence on links between poststroke dementia and inflammation. RECENT FINDINGS: Although there are still no treatments for poststroke dementia, recent evidence has improved our understanding that stroke increases the risk of incident dementia and worsens cognitive trajectory for at least a decade afterwards. Within approximately the first year dementia onset is associated with stroke severity and location, whereas later absolute risk is associated with more traditional dementia risk factors, such as age and imaging findings. The molecular mechanisms that underlie increased risk of incident dementia in stroke survivors remain unproven; however new data in both human and animal studies suggests links between cognitive decline and inflammation. These point to a model where chronic brain inflammation, provoked by inefficient clearance of myelin debris and a prolonged innate and adaptive immune response, causes poststroke dementia. These localized immune events in the brain may themselves be influenced by the peripheral immune state at key times after stroke. SUMMARY: This review recaps clinical evidence on poststroke dementia, new mechanistic links between the chronic inflammatory response to stroke and poststroke dementia, and proposes a model of immune-mediated neurodegeneration after stroke.

Selective angiography with the possibility of thrombolysis in patients with central retinal artery occlusion.

PURPOSE: Describe the clinical finding and course of treatment in patients with a sudden decrease in visual function due to an acute occlusion of the arteria centralis retinae. Patients were primarily indicated for selective angiography with thrombolysis of the ophthalmic artery. MATERIALS AND METHODS: Medical documentation of two patients with acute central retinal artery occlusion with a time duration of up to 5 hours was evaluated retrospectively. The diagnosis of central retinal artery occlusion was determined on the basis of a detailed ophthalmological examination in arteficial mydriasis. The initial best-corrected visual acuity (BCVA) were hand movement in front of the eye with uncertain light projection in first patient and no light perception in the second patient. In both cases a relative afferent pupillary defect of the 4th degree was present with the onset of the ischemic macular edema and an incipient development of the cherry red spot. After evaluation of the overall condition, laboratory findings, exclusion of cancer and surgery in the last three months, a selective angiography of ophthalmic artery and thrombolysis in collaboration with the intervention radiologist were performed.   Results: First patient with a better initial visual acuity, selective angiography demonstrated a decrease in flow in the central retinal artery with subsequent improvement in haemodynamic ratios after application of 12 ml of recombinant tissue plasminogen activator (Alteplase). The BCVA improved to 1/ 60 after interventional procedure. We did not experience any serious treatment side effects during or after intervention. In the second patient, selective angiography of the intracranial arteries and internal carotids revealed the presence of an aneurysm before the ophthalmic artery. Due to the normal flow of the contralateral carotid and the filling of the intracranial vessels on the affected side via the circle of Willis, the internal carotid ligation was performed under the aneurysm. Three months after the surgery BCVA was no light perception and patient had no neurological symptomatology. CONCLUSION: Selective angiography in combination with thrombolysis appears to be a useful imaging as well as therapeutic method for acute central retinal artery occlusion. This technique allows not only to confirm the diagnosis but it can also solve problem causally and improve the visual acuity of the affected person. Sometimes it also helps to clear the cause of the closure and prevent next potential embolization into the intracranial space and possible fatal consequences of CNS involvement or even death.

Effects of an Implementation Intervention to Promote Use of Patient-Reported Outcome Measures on Clinicians' Perceptions of Evidence-Based Practice, Implementation Leadership, and Team Functioning.

INTRODUCTION: Patient-reported outcome measures (PROMs) are administered rarely during rehabilitation hospitalizations because clinicians are unfamiliar with their use and the technology to integrate PROMs into electronic medical records is nascent. This study evaluated an implementation intervention that targeted teams' perceptions of evidence-based practice (EBP), implementation leadership, and team functioning that might facilitate PROM use. METHODS: We compared clinicians' perceptions on three inpatient rehabilitation units, with sequential implementation across units. Clinicians completed the EBP Attitudes Scale, Implementation Leadership Scale, and the Team Functioning Survey before, shortly after, and 1 month after training. RESULTS: Forty-seven clinicians participated, including nurses (27.7%), occupational (21.3%) and physical therapists (21.3%), and two physicians. They worked on spinal cord injury (46.8%), neurologic (40.4%), or pediatric (12.8%) units. EBP Attitude Scale scores improved from preintervention to postintervention and remained above baseline levels at follow-up. The interaction between time and unit was statistically significant for the Divergence subscale such that Pediatric Unit scores increased from preintervention to postintervention and follow-up, while on the spinal cord injury, unit scores increased from preintervention to postintervention, and on the Neurologic Unit scores declined from preintervention to postintervention and follow-up. The EBP Attitudes Requirements score increased at postintervention and follow-up. The Implementation Leadership Scale Proactive score and team functioning survey scores decreased slightly. DISCUSSION: Implementing PROMs had varied effects on EBP attitudes and perceptions of leadership and team functioning. Perceptions across units were distinctive on the Evidence-Based Practice Attitudes Scale Divergence subscale. Introduction of PROMs should consider clinician attitudes regarding EBP as well as implementation leadership and team functioning.

A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction.

Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor α, interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases.