Direct reprogramming of astrocytes to neurons leads to functional recovery after stroke

AbstractStroke is the leading cause of adult disability with few treatment options for stroke survivors. Astrocyte reprogramming to neurons enables the targeted in vivo generation of new cells at the site of injury and represents a novel approach for brain repair. A number of studies have demonstrated successful conversion of astrocytes to neurons in various models of brain injury and disease; however, the impact of this strategy on tissue and functional outcome following stroke is not well established. Using AAV delivery of the transcription factor NeuroD1, we reprogrammed astrocytes 7 days after endothelin-1 induced cortical stroke, and studied the long-term cellular and functional outcomes. We found that by 63 days post-stroke, 20% of neurons in the perilesional cortex were reprogrammed. Furthermore, reprogrammed neurons had matured into regionally appropriate neuronal subtypes. Importantly, this treatment was associated with improved functional outcome using the foot fault test and gait analysis. Together, our findings indicate that in vivo reprogramming is a promising regenerative approach for stroke repair.

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Long term Post-Stroke Functional Outcomes: a comparison of diabetics and non-diabetics

Cerebrovascular Diseases Extra ◽

10.1159/000521442 ◽

2021 ◽

Author(s):

Deidre Anne de Silva ◽

Kaavya Narasimhalu ◽

Ian Wang Huang ◽

Fung Peng Woon ◽

John C. Allen ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Outcome ◽

Functional Outcomes ◽

Age Group ◽

Stroke Patients ◽

Poor Functional Outcome ◽

Post Stroke ◽

The Impact

Introduction: Diabetes mellitus (DM) is known to influence outcomes in the short-term following stroke. However, the impact of DM on long-term functional outcomes after stroke is unclear. We compared functional outcomes periodically over 7 years between diabetic and non-diabetic ischemic stroke patients and investigated the impact of DM on the long-term trajectory of post-stroke functional outcomes. We also studied the influence of age on the diabetes-functional outcome association. Methods: This is a longitudinal observational cohort study of 802 acute ischemic stroke patients admitted to the Singapore General Hospital from 2005 to 2007. Functional outcomes were assessed using the modified Rankin Scale (mRS) with poor functional outcome defined as mRS≥3. Follow-up data was determined at 6 months and at median follow-up durations of 29 and 86 months. Results: Among the 802 ischemic stroke patients studied (mean age 64 ± 12 years, male 63%), 42% had DM. In regression analyses adjusting for covariates, diabetic patients were more likely to have poor functional outcomes at 6 months (OR=2.12, 95% CI: 1.23–3.67) and at median follow-up durations of 29 months (OR=1.96, 95% CI: 1.37–2.81) and 86 months (OR=2.27, 95% CI: 1.58–3.25). In addition, age modulated the effect of DM, with younger stroke patients (≤65 years) more likely to have long term poor functional outcome at the 29-month (p=0.0179) and 86-month (p=0.0144) time points. Conclusions: DM was associated with poor functional outcomes following ischemic stroke in the long term with the effect remaining consistent throughout the 7-year follow-up period. Age modified the effect of DM in the long term, with an observed increase in risk in the ≤65 age group but not in the >65 age group.

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Abstract TP36: Impact of Intracranial Hemorrhage After Endovascular Treatment on Long-Term Functional Outcomes in Patients With Acute Large Vessel Occlusion: Insights From RESCUE- Japan Registry-2

Stroke ◽

10.1161/str.51.suppl_1.tp36 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Norito Kinjo ◽

Kazutaka Uchida ◽

Shinichi Yoshimura ◽

Nobuyuki Sakai ◽

Hiroshi Yamagami ◽

...

Keyword(s):

Functional Outcome ◽

Intracranial Hemorrhage ◽

Functional Outcomes ◽

Large Vessel ◽

Prognostic Impact ◽

Large Vessel Occlusion ◽

Vessel Occlusion ◽

Good Outcome ◽

The Impact

Background and Purpose: Endovascular therapy (EVT) for acute large vessel occlusion (LVO) is currently standard therapy, but it was associated with a higher incidence of intracranial hemorrhage (ICH) compared to conservative therapy. We investigated the impact of ICH within 72 hours on functional outcome at 90 days in patients with EVT for acute LVO. Methods: RESCUE-Japan Registry-2 was a multicenter registry enrolled 2420 consecutive patients with acute LVO within 24 hours of onset. We analyzed patients who received EVT and compared the functional outcomes between those with ICH (ICH group) and without ICH (No-ICH group) within 72 hours after onset. We estimated the adjusted odds ratio (OR) for good functional outcome as mRS 0-2 and mortality. We also explored the prognostic impact of symptomatic ICH (SICH) among those with ICH. Results: Among 2420 patients in the registry, 1281 received EVT and mean age was 75 years, and 759 (59.2%) were men. ICH occurred in 332 patients (25.9%). Good outcome was observed 80 patients (24.0%) and 454 patients (47.9%) in the ICH and No-ICH group, respectively, and the adjusted OR for good outcome of ICH group compared to No-ICH group was 0.30 (95% CI 0.22-0.42, p<0.0001). However, the mortalities within 90 days were not significantly different between groups (adjusted OR 1.13; 95% CI 0.72-1.76, p=0.59). SICH was observed in 35 patients (10.5%) among 332 patients with ICH, and the good outcomes were 8.6% and 25.9 % in patients with SICH and asymptomatic ICH (AICH), respectively (p=0.02). Mortality at 90 days were 31.4% and 7.0% in patients with SICH and AICH, respectively (p<0.0001). Conclusion: The functional outcomes at 90 days after onset was significantly worse in patients suffered ICH than the counterparts after EVT for acute LVO. However, the mortality rates were generally similar between those with and without ICH. Among patients with ICH, mortality was higher in patients with SICH, but mortality of the patients with AICH was similar to those without ICH.

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Scaphoid Nonunion Is a Disabling Problem in a Military Population

Hand ◽

10.1177/15589447211003177 ◽

2021 ◽

pp. 155894472110031

Author(s):

Nicholas H. Lake ◽

Rafae Khan ◽

Kyle W. Mombell ◽

Mary Fergus ◽

Dominic Gomez-Leonardelli

Keyword(s):

Functional Outcome ◽

Military Service ◽

Functional Outcomes ◽

High Rate ◽

Scaphoid Nonunion ◽

Military Population ◽

Outcome Scores ◽

The Mean ◽

Return To Duty

Background Scaphoid nonunion can occur in up to 55% of displaced scaphoid fractures. Long-term functional outcomes of this injury are lacking. In addition, no study has published rate of return to active military service after this injury. Our goal was to educate providers and patients on expected functional outcomes and return to duty after treatment of scaphoid nonunion. Methods We conducted a retrospective review of patients who underwent scaphoid nonunion repair at our institution from 2008 to 2017. The primary outcome measures were union rates, return to duty rates, and functional outcome scores obtained by telephone call. A total of 144 patients were included and 40 responded to our call for long-term follow-up. Results A total of 72% of patients achieved union after surgery, 18% required revision surgery, and 74% of patients were able to return to full duty after surgery. However, this number progressively decreased at 1, 2, and 5 years after surgery. At an average of 5.9 years after surgery, the mean Quick Disabilities of the Arm, Shoulder, and Hand (qDASH) score was 23.9. The mean qDASH for patients who achieved union (21.9) was significantly lower than those with persistent nonunion (29.2) ( P = .0115). Conclusion Scaphoid nonunion is a difficult problem in the military. We found a high rate of persistent nonunion often requiring revision to partial or full wrist arthrodesis. In addition, our long-term functional outcome scores demonstrate significant disability after this injury, even when union is achieved. This information can help us better counsel our patients and set expectations after treatment of this injury.

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Effectiveness of Combined External Ventricular Drainage with Intraventricular Fibrinolysis for the Treatment of Intraventricular Haemorrhage with Acute Obstructive Hydrocephalus

Cerebrovascular Diseases Extra ◽

10.1159/000501530 ◽

2019 ◽

Vol 9 (2) ◽

pp. 77-89 ◽

Cited By ~ 3

Author(s):

Chinh Quoc Luong ◽

Anh Dat Nguyen ◽

Chi Van Nguyen ◽

Ton Duy Mai ◽

Tuan Anh Nguyen ◽

...

Keyword(s):

Functional Outcome ◽

Functional Outcomes ◽

Low Dose ◽

Obstructive Hydrocephalus ◽

Intraventricular Haemorrhage ◽

External Ventricular Drainage ◽

Risk Of Death ◽

Good Functional Outcome ◽

Intraventricular Fibrinolysis ◽

The Impact

Background: Intraventricular haemorrhage (IVH) patients with acute obstructive hydrocephalus (AOH) who require external ventricular drainage (EVD) are at high risk for poor outcomes. Intraventricular fibrinolysis (IVF) with low-dose recombinant tissue plasminogen activator (rtPA) can be used to improve patient outcomes. Here, we evaluated the impact of IVF on the risk of death and the functional outcomes in IVH patients with AOH. Methods: This prospective cohort study included IVH patients with hypertensive intracranial haemorrhage complicated by AOH who required EVD. We evaluated the risk of death and the functional outcomes at 1 and 3 months, with a specific focus on the impact of combined EVD with IVF by low-dose rtPA. Results: Between November 30, 2011 and December 30, 2014, 80 patients were included. Forty-five patients were treated with EVD alone (EVD group) and 35 received IVF (EVD+IVF group). The 30- and 90-day mortality rates were lower in the EVD+IVF group than in the EVD group (42.2 vs. 11.4%, p = 0.003, and 62.2 vs. 20%, p < 0.001, respectively). The Graeb scores were significantly lower in the EVD+IVF group than in the EVD group (p ≤ 0.001) during the first 3 days and on day 7 after assignment. The 30-day good functional outcome (modified Rankin Scale [mRS] score 0–3) was also higher in the EVD+IVF group than in the EVD group (6.7 vs. 28.6%, p = 0.008). However, the 90-day good functional outcome (mRS score 0–3) did not significantly increase in the EVD+IVF group (30.8% in the EVD group vs. 51.6% in the EVD+IVF group, p = 0.112). Conclusions: In our prospective observational study, EVD+IVF was associated with a lower risk of death in IVH patients. EVD+IVF improved the chance of having a good functional outcome at 1 month; however, this result was no longer observed at 3 months.

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Long-Term Effects of Decompressive Craniectomy on Functional Outcomes after Traumatic Brain Injury: A Multicenter Study

The American Surgeon ◽

10.1177/000313481808400844 ◽

2018 ◽

Vol 84 (8) ◽

pp. 1314-1318 ◽

Cited By ~ 1

Author(s):

Eliza Moskowitz ◽

Claudia I. Melendez ◽

Julie Dunn ◽

Abid D. Khan ◽

Richard Gonzalez ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Confidence Interval ◽

Functional Outcome ◽

Decompressive Craniectomy ◽

Functional Outcomes ◽

Structured Interview ◽

Good Functional Outcome

Decompressive craniectomy (DC) is a surgical modality sometimes used in the management of elevated intracranial pressure. Questions remain as to its long-term benefits in traumatic brain injury patients. The extended Glasgow Outcome Scale (eGOS) is a scoring system based on a structured interview that allows for consistent and reproducible measurement of long-term functional outcomes. The purpose of this study was to determine the eGOS score of post-craniectomy patients after discharge and stratify survivors based on outcome. A multicenter review of patients who underwent DC was performed. Survivors underwent a phone survey at which time the eGOS was calculated. Patients with an eGOS ≥ 5 were considered to have a good functional outcome. Fifty-four patients underwent DC. Age (OR 1.038; confidence interval 1.003–1.074) and Glasgow Coma Scale (OR 0677; confidence interval 0.527–0.870) were predictors of mortality. Patients who were available for follow-up (n = 13) had poor functional outcomes at discharge (eGOS = 3); however, this improved at the time of follow-up survey (eGOS = 5; P = 0.005). DC is a controversial operation with high mortality and uncertain benefit. Among our cohort, the eGOS score was significantly higher at follow-up survey than it was at discharge. Although the mortality was high, if patients survived to discharge, most had a good functional outcome at follow-up survey.

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Incidence and Prognostic Impact of Intracranial Hemorrhage after Endovascular Treatment for Acute Large Vessel Occlusion

Cerebrovascular Diseases ◽

10.1159/000510970 ◽

2020 ◽

Vol 49 (5) ◽

pp. 540-549

Author(s):

Norito Kinjo ◽

Shinichi Yoshimura ◽

Kazutaka Uchida ◽

Nobuyuki Sakai ◽

Hiroshi Yamagami ◽

...

Keyword(s):

Endovascular Treatment ◽

Functional Outcome ◽

Intracranial Hemorrhage ◽

Functional Outcomes ◽

Large Vessel ◽

Prognostic Impact ◽

Large Vessel Occlusion ◽

Vessel Occlusion ◽

Scale Scores ◽

The Impact

Introduction: Endovascular treatment (EVT) is effective against acute cerebral large vessel occlusion (LVO). However, it has been associated with a high incidence of intracranial hemorrhage (ICH). Because the incidence of ICH and prognostic impact of ICH were not scrutinized in general patients, we investigated the impact of ICH after EVT on functional outcome at 90 days in patients with acute LVO. Methods: RESCUE-Japan Registry 2 was a multicenter registry that enrolled 2,420 consecutive patients with acute LVO within 24 h of onset. We analyzed 1,281 patients who received EVT and compared the functional outcomes between those with and without ICH (ICH and no-ICH groups, respectively) within 24 h after EVT. We explored the factors associated with ICH and prognostic impact of symptomatic ICH (SICH) among patients with ICH. We estimated the adjusted odds ratios (ORs) for good functional outcome as modified Rankin Scale scores 0–2 and mortality. We also explored the prognostic impact of symptomatic ICH (SICH) among patients with ICH. Results: ICH occurred in 333 patients (26.0%). Several factors such as perioperative edaravone, stent retriever, and baseline glucose were associated with development of ICH within 24 h. A good outcome was observed in 80 (24.0%) and 454 (47.9%) patients in the ICH and no-ICH groups, respectively, and the adjusted OR was 0.3 (95% confidence interval [CI] = 0.2–0.5, p < 0.0001). Incidence of mortality within 90 days was not significantly different between the groups (adjusted OR 1.2; 95% CI: 0.7–1.9, p = 0.5). SICH was observed in 36 (10.8%) of 333 patients with ICH, and the good outcomes were 8.3 and 25.9% in patients with SICH and asymptomatic ICH (AICH), respectively (p = 0.02). Mortality at 90 days was 30.6 and 7.1% in patients with SICH and AICH, respectively (p < 0.0001). Conclusions: The functional outcomes at 90 days were significantly worse in patients who developed ICH after receiving EVT for acute LVO, but the mortality was generally similar.

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Antidiabetic Effects of Bisamide Derivative of Dicarboxylic Acid in Metabolic Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21030991 ◽

2020 ◽

Vol 21 (3) ◽

pp. 991 ◽

Cited By ~ 1

Author(s):

Angelina Vladimirovna Pakhomova ◽

Vladimir Evgenievich Nebolsin ◽

Olga Victorovna Pershina ◽

Vyacheslav Andreevich Krupin ◽

Lubov Alexandrovna Sandrikina ◽

...

Keyword(s):

Metabolic Syndrome ◽

Stem Cells ◽

Dicarboxylic Acid ◽

Metabolic Disorders ◽

Biological Effects ◽

Treatment Options ◽

The Metabolic Syndrome ◽

Pancreatic Stem Cells ◽

The Impact

In clinical practice, the metabolic syndrome can lead to multiple complications, including diabetes. It remains unclear which component of the metabolic syndrome (obesity, inflammation, hyperglycemia, or insulin resistance) has the strongest inhibitory effect on stem cells involved in beta cell regeneration. This makes it challenging to develop effective treatment options for complications such as diabetes. In our study, experiments were performed on male C57BL/6 mice where metabolic disorders have been introduced experimentally by a combination of streptozotocin-treatment and a high-fat diet. We evaluated the biological effects of Bisamide Derivative of Dicarboxylic Acid (BDDA) and its impact on pancreatic stem cells in vivo. To assess the impact of BDDA, we applied a combination of histological and biochemical methods along with a cytometric analysis of stem cell and progenitor cell markers. We show that in mice with metabolic disorders, BDDA has a positive effect on lipid and glucose metabolism. The pancreatic restoration was associated with a decrease of the inhibitory effects of inflammation and obesity factors on pancreatic stem cells. Our data shows that BDDA increases the number of pancreatic stem cells. Thus, BDDA could be used as a new compound for treating complication of the metabolic syndrome such as diabetes.

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The Rapid and Accurate Categorisation of Critically Ill Patients (RACE) to Identify Outcomes of Interest for Longitudinal Studies: A Feasibility Study

Anaesthesia and Intensive Care ◽

10.1177/0310057x1704500411 ◽

2017 ◽

Vol 45 (4) ◽

pp. 476-484 ◽

Cited By ~ 1

Author(s):

A. M. Deane ◽

C. L. Hodgson ◽

P. Young ◽

L. Little ◽

V. Singh ◽

...

Keyword(s):

Gold Standard ◽

Functional Outcomes ◽

Clinical Approach ◽

Baseline Assessment ◽

Inception Cohort ◽

Eligibility Criteria ◽

Standard Assessment ◽

The Impact ◽

Blinded Assessor

The capacity to measure the impact of an intervention on long-term functional outcomes might be improved if research methodology reflected our clinical approach, which is to individualise goals of care to what is achievable for each patient. The objective of this multicentre inception cohort study was to evaluate the feasibility of rapidly and accurately categorising patients, who were eligible for simulated enrolment into a clinical trial, into unique categories based on premorbid function. Once a patient met eligibility criteria a rapid ‘baseline assessment’ was conducted to categorise patients into one of eight specified groups. A subsequent ‘gold standard’ assessment was made by an independent blinded assessor once patients had recovered sufficiently to allow such an assessment to occur. Accuracy was predefined as agreement in >80% of assessments. One hundred and twenty-two patients received a baseline assessment and 104 (85%) were categorised to a unique category. One hundred and six patients survived to have a gold standard assessment performed, with 100 (94%) assigned to a unique category. Ninety-two patients had both a baseline and gold standard assessment, and these agreed in 65 (71%) patients. It was not feasible to rapidly and accurately categorise patients according to premorbid function.

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Long Term Pharmacological Perturbation of Autophagy in Mice: Are HCQ Injections a Relevant Choice?

Biomedicines ◽

10.3390/biomedicines8030047 ◽

2020 ◽

Vol 8 (3) ◽

pp. 47 ◽

Cited By ~ 1

Author(s):

Jean-Daniel Masson ◽

Benoit Blanchet ◽

Baptiste Periou ◽

François-Jérôme Authier ◽

Baharia Mograbi ◽

...

Keyword(s):

Mouse Models ◽

In Vivo Studies ◽

Loss Of Function ◽

Evolutionarily Conserved ◽

Atg Genes ◽

Conditional Inhibition ◽

The Impact ◽

Catabolic Process

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved catabolic process whose loss-of-function has been linked to a growing list of pathologies. Knockout mouse models of key autophagy genes have been instrumental in the demonstration of the critical functions of autophagy, but they display early lethality, neurotoxicity and unwanted autophagy-independent phenotypes, limiting their applications for in vivo studies. To avoid problems encountered with autophagy-null transgenic mice, we investigated the possibility of disturbing autophagy pharmacologically in the long term. Hydroxychloroquine (HCQ) ip injections were done in juvenile and adult C57bl/6j mice, at range doses adapted from the human malaria prophylactic treatment. The impact on autophagy was assessed by western-blotting, and juvenile neurodevelopment and adult behaviours were evaluated for four months. Quite surprisingly, our results showed that HCQ treatment in conditions used in this study neither impacted autophagy in the long term in several tissues and organs nor altered neurodevelopment, adult behaviour and motor capabilities. Therefore, we recommend for future long-term in vivo studies of autophagy, to use genetic mouse models allowing conditional inhibition of selected Atg genes in appropriate lineage cells instead of HCQ treatment, until it could be successfully revisited using higher HCQ doses and/or frequencies with acceptable toxicity.

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In Vivo Performance of a Novel, Anatomically Shaped, Total Meniscal Prosthesis Made of Polycarbonate Urethane: A 12-Month Evaluation in Goats

The American Journal of Sports Medicine ◽

10.1177/0363546517713687 ◽

2017 ◽

Vol 45 (12) ◽

pp. 2824-2834 ◽

Cited By ~ 8

Author(s):

Anne C.T. Vrancken ◽

Gerjon Hannink ◽

Wojciech Madej ◽

Nico Verdonschot ◽

Tony G. van Tienen ◽

...

Keyword(s):

Treatment Options ◽

Wear Particles ◽

The Novel ◽

Stifle Joint ◽

Physiological Loading ◽

Polycarbonate Urethane ◽

Sham Surgery

Background: Injury or loss of the meniscus generally leads to degenerative osteoarthritic changes in the knee joint. However, the treatment options for symptomatic patients with total meniscectomy are limited. Therefore, we developed a novel, anatomically shaped, total meniscal implant made of polycarbonate urethane. Purpose: To evaluate the in vivo performance of this novel total meniscal implant. The assessment particularly focused on the implant’s response to long-term physiological loading in a goat model and its chondroprotective capacity in comparison to clinically relevant controls. Study Design: Controlled laboratory study. Methods: Surgery was performed to the stifle joint of 26 female Saanen goats, subdivided into 4 groups: implant, allograft, total meniscectomy, and sham surgery. The sham group’s contralateral joints served as nonoperated controls. After 12 months of follow-up, investigators evaluated implant wear, deformation, and the histopathological condition of the synovium and cartilage. Results: Wear of the implant’s articulating surfaces was minimal, which was confirmed by the absence of wear particles in the synovial fluid. Implant deformation was limited. However, one implant failed by complete tearing of the posterior horn extension. No differences in cartilage histopathological condition were observed for the implant, allograft, and meniscectomy groups. However, locally, the cartilage scores for these groups were significantly worse than those of the nonoperated controls. Conclusion: Whereas this study demonstrated that the novel implant is resistant to wear and that deformation after 12 months of physiological loading is acceptable, reinforcement of the implant horns is necessary to prevent horn failure. Although the implant could not protect the cartilage from developing degenerative changes, the progression of damage was similar in the allograft group. Clinical Relevance: This novel polycarbonate urethane implant may have the potential to become an alternative treatment for symptomatic patients with total meniscectomy.

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