Significant Functional Recovery Research Articles

QS6: Collagen-glycosaminoglycans Scaffold Can Improve Muscle Function Recovery After Volumetric Muscle Loss Injury in Rat Model

Propose:Skeletal muscle regenerative capacity fails in restoring muscle function following major injuries in which significant skeletal muscle is lost or damaged. As such, volumetric muscle loss (VML), ultimately results in permanent disability. Therapeutic options are limited in VML and currently no standard of care exists. Biodegradable scaffolds hold great potentials in the regeneration of lost muscle tissue by replacing the lost structural framework of the defect. In this study we aim to evaluate the effects of a porous collagen-glycosaminoglycans scaffold (CGS) on muscle function recovery following VML injury in a rat model.Methods:Fifteen male 12-week old Sprague-Dawley rats were randomly divided into three groups of 5 rats in each: 1) Sham group, 2) VML Untreated (control) group, and 3) VML+CGS group. A standard model of VML injury was performed to bilateral Tibialis Anterior (TA) muscles in VML Untreated and VML+CGS groups. The muscle defect in VML+CGS group was filled with 3 sheets of CGS cuts while the muscle defects in VML control group left untreated. Animals in Sham group underwent the same surgical procedure (skin and fascia opening and closure) but without any muscle injury. Pick isometric twitch and tetanus forces of foot dorsiflexion were measured in vivo prior, immediately after, and four weeks post injury using a dual mode muscle lever system. In situ TA muscle twitch and tetanic contraction strengths were also determined six weeks after injury.Results:Prior, and immediately after injury no statistically significant differences was seen between VML Untreated and VML+CGS groups in terms of the means of twitch and tetanus foot isometric dorsiflexion forces. Four weeks after injury, TA of VML+ CGS group showed significant functional recovery as compared with VML Untreated group in twitch (76 ± 22.7% vs 51.3 ± 22.3%, p<0.01) and tetanus (77.4 ± 22.1% vs 59.8 ± 22.4%, p<0.05) foot dorsiflexion forces. In situ muscle strength measurements of TA at six weeks post injury, also showed significantly higher twitch (35.2 ± 12.5 mN/mm2 vs 23.7 ± 6.9 mN/mm2, p<0.05) and tetanus (115.0 ± 35.3 mN/mm2 vs 87.9 ± 20 mN/mm2, p<0.05) forces in TA of VML+CGS group when compared with the VML Untreated group. On histology of the TA performed six weeks following initial injury, placement of CGS decreased fibrosis across the injury, as defined as percentage of positive area in trichrome staining compared with VML Untreated group (1.3 ± 0.1% vs. 7.1 ± 1.3%, p<0.01). In addition, immunofluorescence tissue staining confirmed positive myosin heavy chain staining within the scaffold, indicating the formation of nascent myofibers within the area of injury.Conclusions:Application of CGS to the muscle defect following VML injury can improve muscle function recovery, limit fibrosis, and promote muscle regeneration in rodent model. These findings can foster future research in larger animals and human subjects.*p<0.05, **p<0.01. Error bars: Standard Deviations.

Transneuronal delivery of designer cytokines: perspectives for spinal cord injury.

Transneuronal delivery of designer cytokines: perspectives for spinal cord injury.

Long term clinical outcome following decompressive surgery for Cauda Equina Syndrome

Study design: Retrospective study with prospective long-term clinical follow-up.&#x0D; Background: Cauda equina syndrome (CES) is a neurosurgical emergency, mostly caused by herniated lumbar disc for which urgent surgical decompression is indicated. Data on long-term clinical outcome of bladder, bowel &amp; sexual function following decompression are elusive.&#x0D; Aim: To evaluate the effectiveness of surgical decompression on recovery of CES symptoms at long-term follow-up &amp; role of timing of surgery on the outcome.&#x0D; Methods: Records of 35 CES patients who underwent surgical decompression for herniated lumbar disc during a five years period retrospectively analysed &amp; patients called for follow-up visits. Outcome measures comprised of history &amp; clinical examination pertinent to bladder, bowel &amp; sexual function.&#x0D; Results: Twenty-four patients (68.5%) were included for final evaluation who attended follow-up visits, with a minimum follow-up period of one year. Most common complaint at presentation was bladder dysfunction (100%) with urinary retention in 16 patients (66.6%), faecal incontinence in 11 (45.8%), saddle anaesthesia in 22 (91.6%) &amp; erectile dysfunction in 6 patients (out of 15 males). Only four patients underwent surgery within 48 hours of CES symptom onset, rest cases after 48 hours duration. At follow-up, bladder dysfunction present in 33.3% with urinary retention in 16.6%. Faecal incontinence persisted in 4 patients (16.6%) &amp; saddle anaesthesia in 7 (29.1%). Sexual dysfunction was the most persistent complaint.&#x0D; Conclusion: Long-term follow-up shows significant recovery of sphincteric function in CES patients after surgical decompression. Urinary &amp; bowel dysfunction improve significantly. Timing to surgery didn’t affect the long-term outcome.

Prognostic Value of Investigating Neuron-Specific Enolase in Patients with Ischemic Stroke.

The aim of the study was to assess the prognostic value of the plasma neuron-specific enolase (NSE) level as a predictor of functional outcome and motor function recovery in the acute period of ischemic stroke (IS).Materials and MethodsFifty patients with IS have been examined. On admission to the hospital and at 12–14 days after stroke onset, a clinical and neurological examination have been carried out with the supplementary quantitative assessment of neurological deficit severity according to the National Institutes of Health Stroke Scale (NIHSS), functional outcome according to the Modified Rankin Scale, and Rivermead Mobility Index. Enzyme immunoassay was used to determine NSE concentration in blood plasma in the acute period of the disease.ResultsThe NSE level in patients’ blood plasma in the first 48 h after stroke onset positively correlates with the ischemic focus volume (r=0.49; p=0.003) and the severity of neurological symptoms (according to NIHSS) (r=0.33; p=0.02). NSE less than 2 ng/ml in the acute disease period is a predictor of good functional outcome 12–14 days after stroke onset (OR=12.4; р=0.006). The NSE level >2.6 ng/ml is associated with a high likelihood of lethal outcome.Neurological deficit below 15 according to NIHSS as well as the NSE level <2 ng/ml in the acute IS period are estimated as prognostic factors of significant recovery of motor function at 2 weeks after disease onset (OR=5.8; р=0.02).ConclusionDetermination of NSE in blood plasma makes it possible to predict functional outcome of the disease development and the recovery of motor function in patients with IS.

Sustained Chemosensory Dysfunction during the COVID-19 Pandemic

Introduction: Chemosensory dysfunction (CD) has proven valuable in prediction of COVID-19, as it is a frequent and specific symptom of the disease. The aim of this study was to investigate the duration of CD in patients with sudden subjective olfactory and/or gustatory loss during the SARS-CoV-2 pandemic. The secondary aim was to identify possible prognostic factors for the duration of CD. Methods: An online baseline questionnaire was designed to assess subjective CD. Three rounds of follow-up questionnaires were sent out to any participants with persistent CD in 6-week intervals, prospectively assessing subjective chemosensory function and extending the follow-up time of this cohort significantly. Results: In total, 467 participants completed the baseline questionnaire. The most significant improvement and recovery of chemosensory function was observed within the first month after the initial loss. Rates became stagnant after about 2 months, and only little improvement and recovery was seen after 2–4 months. After a mean follow-up of 95.9 days (olfactory dysfunction) and 94.0 days (gustatory dysfunction), 86.7% of participants reported gustatory improvement and 82.6% reported olfactory improvement, while 55.0% reported full gustatory recovery and 43.8% reported full olfactory recovery. Female gender was associated with better improvement of gustatory function. High subjective severity of chemosensory loss was associated with lower rates of olfactory and gustatory recovery as well as improvement of olfactory function. Young age was not associated with a better prognosis. Discussion/Conclusion: Rates of improvement and recovery of chemosensory function decreased after 2–4 months after initial chemosensory loss, possibly indicating that prolonged and perhaps permanent chemosensory loss may be a complication of SARS-CoV-2 infections. High subjective severity of CD may worsen the prognosis for improvement and recovery of chemosensory function.

Slow but Evident Recovery from Neocortical Dysfunction and Cognitive Impairment in a Series of Chronic COVID-19 Patients.

Cognitive impairment is a frequent complaint in coronavirus disease 2019 (COVID-19) and can be related to cortical hypometabolism on 18F-FDG PET at the subacute stage. However, it is unclear if these changes are reversible. Methods: We prospectively assessed the Montreal Cognitive Assessment scores and 18F-FDG PET scans of 8 COVID-19 patients at the subacute stage (once no longer infectious) and the chronic stage (˜6 mo after symptom onset). The expression of the previously established COVID-19-related covariance pattern was analyzed at both stages to examine the time course of post-COVID-19 cognitive impairment. For further validation, we also conducted a conventional group analysis. Results: Follow-up 18F-FDG PET revealed that there was a significant reduction in the initial frontoparietal and, to a lesser extent, temporal hypometabolism and that this reduction was accompanied by a significant improvement in cognition. The expression of the previously established COVID-19-related pattern was significantly lower at follow-up and correlated inversely with Montreal Cognitive Assessment performance. However, both 18F-FDG PET and cognitive assessment suggest a residual impairment. Conclusion: Although a significant recovery of regional neuronal function and cognition can be clearly stated, residuals are still measurable in some patients 6 mo after manifestation of COVID-19. Given the current pandemic situation and tremendous uncertainty concerning the long-term effects of COVID-19, the present study provides novel insights of the highest medical and socioeconomic relevance.

Intraspinal Administration of Netrin-1 Promotes Locomotor Recovery after Complete Spinal Cord Transection.

Complete spinal cord lesions interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. In particular, the interruption of connections with the neurons at lumbar segments after thoracic injuries impairs voluntary body control below the injury. The failure of spontaneous regrowth of transected axons across the lesion prevents the reconnection and reinnervation of the neuronal targets. At present, the only treatment in humans that has proven to promote some degree of locomotor recovery is physical therapy. The success of these strategies, however, depends greatly on the type of lesion and the level of preservation of neural tissue in the spinal cord after injury. That is the reason it is key to design strategies to promote axonal regrowth and neuronal reconnection. Here, we test the use of a developmental axon guidance molecule as a biological agent to promote axonal regrowth, axonal reconnection, and recovery of locomotor activity after spinal cord injury (SCI). This molecule, netrin-1, guides the growth of the corticospinal tract (CST) during the development of the central nervous system. To assess the potential of this molecule, we used a model of complete spinal cord transection in rats, at thoracic level 10-11. We show that in situ delivery of netrin-1 at the epicenter of the lesion: (1) promotes regrowth of CST through the lesion and prevents CST dieback, (2) promotes synaptic reconnection of regenerated motor and sensory axons, and (3) preserves the polymerization of the neurofilaments in the sciatic nerve axons. These anatomical findings correlate with a significant recovery of locomotor function. Our work identifies netrin-1 as a biological agent with the capacity to promote the functional repair and recovery of locomotor function after SCI. These findings support the use of netrin-1 as a therapeutic intervention to be tested in humans.

Early Robotic-Assisted Laparoscopic Pyeloplasty for Infants Under 3 Months With Severe Ureteropelvic Junction Obstruction.

Objective: To present our primary experience of robotic-assisted laparoscopic pyeloplasty (RALP) for severe ureteropelvis junction obstruction (UPJO) infants under 3 months.Methods: We performed a retrospective study of 9 infants under 3 months who underwent RALP for severe UPJO between April 2017 and March 2019 in our center. The severe UPJO was defined as infants with severe hydronephrosis (Society of Fetal Urology grades III or IV, anteroposterior diameter >3 cm or split renal function <40% or T 1/2 >20 min) involving bilateral, solitary kidney, or contralateral renal hypoplasia UPJO at the same time. All clinical, perioperative, and postoperative information was collected.Results: There were four bilateral UPJO cases, two solitary kidney UPJO cases and three unilateral UPJO with contralateral renal hypoplasia cases included. One single surgeon performed RALP on all of the infants. The mean age of the infants was 1.62 ± 0.54 months. The mean operative time was 109.55 ± 10.47 min. The mean estimated blood loss was 19.29 ± 3.19 ml, and the mean length of hospital stay was 5.57 ± 0.73 days. According to the ultrasonography results, all patients had a significant recovery of renal function at 12 months after the operation.Conclusions: To maximize the protection of renal function, early RALP is a safe and feasible option for the treatment of severe UPJO in infants under 3 months.

Platelet-rich plasma injection vs corticosteroid injection for conservative treatment of rotator cuff lesions: A systematic review and meta-analysis.

Background:To explore the effectiveness of platelet-rich plasma (PRP) injection regarding functional recovery, pain relief, and range of motion (ROM) of shoulder compared with the corticosteroid injection in patients with rotator cuff lesions treated non-operatively.Methods:An electronic literature search was performed by 2 authors in the PubMed, Embase, Cochrane Library, and Web of Science databases to identify relevant randomized controlled trial (RCTs) that were published up to July 20, 2020. The quality of the included RCTs was evaluated using the approach recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Standardized mean differences (SMDs) or mean differences (MDs) with 95% confidence intervals (CIs) were applied to calculate the pooled effect sizes.Results:Six RCTs were included in this systematic review. Meta-analysis revealed that corticosteroid injection yielded statistically significant superior functional recovery (SMD = −0.80; 95% CI, −1.42 to −0.18; P = .01) and pain relief (MD = 1.59; 95% CI, 0.30–2.89; P = .02) compared with PRP injection for rotator cuff lesions during the short-term follow-up period. However, at the medium-term and long-term follow-up, no statistically significant difference was identified between the 2 groups. Regarding the ROM of shoulder, no statistically significant difference was found between the 2 groups during the whole follow-up period.Conclusions:The current clinical evidence revealed short-term efficacy of corticosteroid injection and no significant medium- to long-term difference between corticosteroid and PRP injection in the treatment of rotator cuff lesions. Additional studies with longer follow-ups, larger sample sizes, and more rigorous designs are needed to draw more reliable and accurate conclusions.

GSNOR and ALDH2 alleviate traumatic spinal cord injury

Traumatic spinal cord injury (SCI) enhances the activity of S-nitrosoglutathione reductase (GSNOR) and inhibits the mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity, resulting in prolonged and sustained pain and functional deficits. This study's objective was to test the hypotheses that GSNOR’s specific inhibitor N6022 mitigates pain and improves functional recovery in a mouse model of SCI. Furthermore, the degree of recovery is enhanced and the rate of recovery is accelerated by an ALDH2 activator Alda-1. Using both wild-type and GSNOR−/− mice, the SCI model deployed for groups was contusion at the T9-T10 vertebral level. The enzymatic activity of GSNOR and ALDH2 was measured, and the expression of GSNOR and ALDH2 was determined by western blot analysis. Functional improvements in experimental animals were assessed with locomotor, sensorimotor, and pain-like behavior tests. Wild-type SCI animals had enhanced GSNOR activity and decreased ALDH2 activity, leading to neurovascular dysfunction, edema, and worsened functional outcomes, including locomotor deficits and pain. Compared to wild-type SCI mice, GSNOR−/− mice had better functional outcomes. Monotherapy with either GSNOR inhibition by N6022 or enhanced ALDH2 activity by Alda-1 correlated well with functional recovery and lessened pain. However, combination therapy provided synergistic pain-relieving effects and more significant functional recovery compared with monotherapy. Conclusively, dysregulations in GSNOR and ALDH2 are among the causative mechanisms of SCI injury. Either inhibiting GSNOR or activating ALDH2 ameliorates SCI. Combining the specific inhibitor of GSNOR (N6022) with the selective activator of ALDH2 (Alda-1) provides greater protection to the neurovascular unit and confers greater functional recovery. The study is novel, and the combination therapy (N6022 + Alda-1) possesses translational potential.

Treatment Effect of Regional Sodium Citrate Anticoagulation in Elderly Patients With High-Risk Bleeding Receiving Continuous Renal Replacement Therapy.

ObjectiveTo investigate the safety and efficacy of regional citrate anticoagulation (RCA) on elderly patients at high risk of bleeding after continuous renal replacement therapy (CRRT).MethodsA total of 31 patients at high risk of bleeding who received CRRT in the intensive care unit were collected. The patients were divided into RCA group (n = 17) and no anticoagulation group (NA, n = 14) according to whether RCA was used or not. The levels of creatinine (Cr), blood urea nitrogen (BUN), prothrombin time (PT), activated partial thromboplastin time (APTT), total calcium (tCa), ionized calcium ion (iCa2+), sodium ion (Na+), bicarbonate ion (HCO3−), tCa/iCa2+ ratio, and pH were observed after treatment. The filter use time, number of filters used, filter obstruction events, clinical outcomes, and safety evaluation indexes were compared post-treatment.ResultsAfter treatment, serum Cr and BUN levels, APTT and PT levels in the RCA group were significantly lower than the NA group. The tCa, iCa2+, HCO3−, tCa/iCa2+, and pH were within the normal range after RCA treatment while Na+ levels saw a significant increase. In the RCA group, the filter using time was significantly longer, with significantly reduced numbers of filter use within 72 h and filter disorder events. Additionally, patients in the RCA group showed significant recovery of renal function and a significant reduction in bleeding events and in-hospital mortality.ConclusionRCA treatment significantly improves clinical outcome of patients at high risk of bleeding after CRRT, safely and effectively prolongs the filter life and avoids coagulation incidences.

Rehabilitation outcomes of persons with severe traumatic brain injury: A cross-sectional survey

Background: The recent literature regarding functional outcomes and the effectiveness of rehabilitation for persons with severe traumatic brain injury (TBI) suggests that these patients are capable of significant functional recovery over a period of months to years after injury. However, the researches concerning this are very limited. Therefore, this study has been conducted to study the rehabilitation outcomes in persons with severe TBI. Objective: To study the rehabilitation outcomes of persons with severe TBI who have completed 8–16 weeks of residential, postacute rehabilitation. Study Design: A cross-sectional survey study design was chosen. Methods: This study was done in Rehabilitation center of Christian Medical College, Vellore. Forty-two patients with severe TBI who completed rehabilitation from January 2014 to November 2016 were selected for this study. Usual care was provided to the participants in a transdisciplinary service delivery model. The Wessex Head Injury Matrix (WHIM), Coma Recovery Scale Revised (CRS-R), Addenbrooke's Cognitive Examination-III (ACE-III), Modified Barthel Index (MBI), Disability Rating Scale, and Community reintegration Questionnaire (CIQ) were used based on the International Classification of Functioning framework to assess the functional gains achieved during and after the rehabilitation process that include admission, discharge, and follow-up. Results: Significant improvements in CRS-R (confidence interval [CI]: −2.879 to − 0.741; P = 0.000), WHIM (CI: −10.42 to − 2.96; P = 0.000), ACE-III (CI: −8.23 to − 26.15; P = 0.000), and MBI (CI: −15.32 to − 39.18; P = 0.000) were found from admission to discharge. A significant change in disability was observed at discharge (CI: 3.79–6.07; P = 0.000) and at follow-up (CI: 0.87–1.75; P = 0.000). Marital status was influencing the CRS-R (CI: −0.82–6.79; P = 0.011) and the WHIM scores (CI: −0.619–14.12; P = 0.047). The mean follow-up CIQ score was 9.77 (standard deviation = 7.01). Only socioeconomic status was influencing CIQ (CI: 2.90–12.98; P = 0.003). Conclusion: Participants showed significant functional gains after the residential, post-acute rehabilitation program. These functional gains were not reflected in their community reintegration.

Aqueous leaf extract from Luehea divaricata Mart. Modulates oxidative stress markers in the spinal cord of rats with neuropathic pain

Ethnopharmacological relevanceReactive oxygen species (ROS) play an important role in neuropathic pain (i.e., pain caused by lesion or disease of the somatosensory system). We showed previously that the aqueous extract prepared from Luehea divaricata leaves, a plant explored by native ethnic groups of Brazil to treat different pathologic conditions, exhibits good antioxidant activity and induces analgesia in rats with neuropathic pain (J Ethnopharmacol, 2020; 256:112761. doi: 10.1016/j.jep.2020.112761). The effect was comparable to that of gabapentin, a drug recommended as first-line treatment for neuropathic pain. However, increasing evidence has indicated the need to accurately determine the oxidative stress level of an individual before prescribing supplemental antioxidants. Aim of the studyThis study assessed the effects of the oral administration of aqueous extract from leaves of L. divaricata on the sciatic functional index (SFI) and spinal-cord pro-oxidant and antioxidant markers of rats with neuropathic pain. Materials and methodsPlacement of four loose chromic thread ligatures around the sciatic nerve produced chronic constriction injury (CCI) of the sciatic nerve, a commonly employed animal model to study neuropathic pain. Aqueous extract from leaves of L. divaricata (100, 300, 500 and 1000 mg/kg), gabapentin (50 mg/kg) and aqueous extract (500 mg/kg) + gabapentin (30 mg/kg) were administrated per gavage daily for 10 or 35 days post-CCI. Antinociception was assessed using the von Frey test while SFI showed functional recovery post-nerve lesion throughout the experimental period. At days 10 and 35 post-surgery, the lumbosacral spinal cord and a segment of the injured sciatic nerve were dissected out and used to determine lipid hydroperoxide levels and total antioxidant capacity (TAC). The spinal cord was also used to determine superoxide anion generation (SAG), hydrogen peroxide (H2O2) levels and total thiol content. ResultsAs expected, the extract, gabapentin and extract + gabapentin induced antinociception in CCI rats. While no significant functional recovery was found at 10 days post-CCI, a significant recovery was found in SFI of extract-treated CCI rats at 21 and 35 days post-CCI. A significant functional recovery was found already at day 10 post-CCI in gabapentin and gabapentin + extract-treated CCI rats. The extract treatment prevented increases in lipid hydroperoxides levels and TAC in injured sciatic nerve, which were found in this tissue of vehicle-treated rats at 10 days post-CCI. Extract also prevented an increase in SAG, H2O2 and lipid hydroperoxides levels in the spinal cord, which were elevated in this tissue of vehicle-treated rats at 10 and 35 days post-CCI. Extract also prevented a decrease in total thiol content and an increase in TAC in the spinal cord of CCI rats in these same time periods. ConclusionsAqueous extract from L. divaricata leaves was demonstrated, for the first time, to improve SFI and modulate oxidative stress markers in injured sciatic nerve and spinal cord of CCI rats. Thus, the antinociceptive effect of the extract involves modulation of oxidative stress markers in injured sciatic nerve and spinal cord.

Degenerative cervical myelopathy presenting as subjective lower limb weakness could be a trap towards misdiagnosis

When patients presenting with subjective lower limb weakness (SLLW) are encountered, it is natural to suspect a lumbar pathology and proceed with related clinical examination, investigations and management. However, SLLW could be a sign of degenerative cervical myelopathy (DCM) due to an evolving cord compression. In such circumstances, if symptoms are not correlated to myelopathy at the earliest, there could be potential complications over time. In this study, we intend to analyse the outcomes after surgical management of the cervical or thoracic cord compression in patients with SLLW. Retrospectively, patients who presented to our center during the years 2010–2016 with sole complaint of bilateral SLLW but radiologically diagnosed to have a solitary cervical or thoracic stenosis, or tandem spinal stenosis and underwent surgical decompression procedures were selected. Their clinical presentation was categorised into three types, myelopathy was graded using Nurick’s grading and JOA scoring; in addition, their lower limb functional status was assessed using the lower extremity functional scale (LEFS). Functional recovery following surgery was assessed at 6 weeks, 3 months, 6 months, one year, and two years. Selected patients (n = 24; Age, 56.4 ± 10.1 years; range 32–78 years) had SLLW for a period of 6.4 ± 3.2 months (range 2–13 months). Their preoperative JOA score was 11.3 ± 1.8 (range 7–15), and LEFS was 34.4 ± 7.7 (range 20–46). Radiological evidence of a solitary cervical lesion and tandem spinal stenosis was found in 6 and 18 patients respectively. Patients gradually recovered after surgical decompression with LEFS 59.8 ± 2.7 (range 56–65) at 1 year and JOA score 13.6 ± 2.7 (range − 17 to 100) at 2 years. The recovery rate at final follow up was 47.5%. Our results indicate the importance of clinically suspecting SLLW as an early non-specific sign of DCM to avoid misdiagnosis, especially in patients without conventional upper motor neuron signs. In such cases, surgical management of the cord compression resulted in significant functional recovery and halted the progression towards permanent disability.

Ultrastructural effects of nerve growth factor and betamethasone on nerve regeneration after experimental nerve injury

ABSTRACT Peripheral nerve injuries (PNI) are an important health problem in the world. In this study, the effects of nerve growth factor (NGF) and betamethasone on nerve regeneration after sciatic nerve crush injury were examined by footprint analysis, electron microscopic, histomorphometric, and biochemical methods. Fifty Wistar rats were divided into five groups as intact control, experimental control, NGF, betamethasone, and NGF+betamethasone combined treatment groups. After the injury, betamethasone was subcutaneously injected into the lesion area of the treatment groups three times during the first day. NGF was subcutaneously injected into the lesion area of treatment groups for 14 days. Footprint analysis was made on 7, 14, 21, 28, and 35 days and after 6 weeks, tissue samples were obtained from all groups. In the experimental control group, there were severe degenerative changes in most of the axons and myelin sheaths of the nerve fibers. Moreover, an increase of MDA levels and a decrease in SOD activities were found in this group. On the other hand, malondialdehyde (MDA) levels decreased, superoxide dismutase (SOD) activities increased and significant motor functional recovery were found in the combined treatment group. The number of axons, axon diameters, and myelin thickness were significantly greater in the combined treatment group when compared with experimental control and other treatment groups. It was thought that nerve regenerative effects of NGF and anti-inflammatory and/or anti-edematous effects of betamethasone could induce functional recovery in the combined treatment group. In conclusion, combined therapy of NGF and betamethasone may be an effective approach for the treatment of PNI.

Abstract 13017: Administration of Intramyocardial Chemokine Induce Myocardial Recovery by Modulating the Acute Inflammatory Response to Ischemia

Introduction: We have previously shown that the exogenously injected chemokines induce robust myocardial recovery and angiogenesis after a myocardial infarction (MI). Angiogenesis, however, is a late response, and the acute cellular drivers of chemokine induced recovery remain elusive. Recently it has been shown that an acute macrophage response is central to post-MI recovery after stem-cell injections. As many chemokines act as immunomodulators, we hypothesized that both angiogenic chemokines (SDF-1) and non-angiogenic chemokines of viral origin (vMIP-II) can similarly elicit a macrophage response. Methods: MI was surgically induced in 39 male and female C57BL/6 mice (6-8 weeks old) by ligation of the left anterior descending coronary artery. Mice were randomly assigned to receive intramyocardial injections of PBS (saline), SDF-1, or vMIP-II. Two hearts from each treatment group were explanted at post-operative day 3 (P3) for single cell suspension preparation. Viable cells were used for single cell RNA sequencing (scRNAseq). Echocardiography was performed for all remaining mice at P7 to assess for functional recovery, and hearts were explanted for histology at P14. Results: Treatment with both SDF-1 and vMIP-II led to significant functional recovery assessed via echocardiography at P7, one week in advance of arteriolar collateralization (Ejection Fraction 0.38 ± 0.14 and 0.50 ± 0.15 in SDF-1 and vMIP respectively; 0.27 ± 0.13 in PBS; t-test adjusted p = 0.023). scRNAseq of 7918 captured cells showed a robust acute inflammatory macrophage response at P3 across treatment groups. A robust expansion of Arginase-1 (Arg1+) macrophages - a known M2 anti-inflammatory subtype - was seen specifically in chemokine treated mice at P3 (9% in PBS vs 16.5% in both SDF-1 and vMIP-II). Conclusions: We show that vMIP-II triggers myocardial recovery similar to SDF-1. Furthermore, we show a robust and consistent Arg1+ macrophage response present in both treatment groups.

Viability and functional recovery after chronic total occlusion percutaneous coronary intervention

Abstract Background Current guidelines advocate viability assessment to guide percutaneous coronary intervention (PCI) of chronic coronary total occlusions (CTO). Purpose Aim of the present study was to evaluate viability as well as global and regional functional recovery after successful CTO PCI using quantitative cardiac magnetic resonance (CMR) imaging. Methods 132 patients with sequential CMR at baseline and 3-months after successful CTO PCI were prospectively recruited between 2013 and 2018. Segmental wall thickening (SWT) and percentage late gadolinium enhancement (LGE) were quantitatively measured per segment. Viability was defined as dysfunctional myocardium (&amp;lt;2.84mm SWT) with no or limited scar (≤50% LGE). Results Significant improvements in left ventricular (LV) ejection fraction (from 48.1±11.8 to 49.5±12.1%, p&amp;lt;0.01), LV end-diastolic volume (from 99.1±31.8 to 95.7±30.2ml, p&amp;lt;0.01), and LV end-systolic volume (from 54.4±30.5 to 51.2±29.3ml, p&amp;lt;0.01) were observed after CTO PCI. CTO segments with viability (N=216, (31%)) demonstrated a significantly higher increase in SWT (0.80±1.39mm) compared to CTO segments with pre-procedural preserved function (N=456 (65%), 0.07±1.43mm, p&amp;lt;0.01) or extensive scar (LGE &amp;gt;50%, N=26 (4%), −0.08±1.09mm, p&amp;lt;0.01). Improvement in SWT was comparable between segments with viability if further stratified to 0, &amp;gt;0–25, and &amp;gt;25–50% hyperenhancement (p=0.94). Patients with ≥2 CTO segments viability showed more SWT increase in the CTO territory compared to patients with 0–1 segment viability (0.49±0.93 vs. 0.12±0.98mm, p=0.03). Conclusions Improvements in LV function and volumes were significant but modest following CTO PCI. Detection of dysfunctional myocardial segments without extensive scar (≤50% LGE) as a marker for viability may aid in identifying subjects with significant regional functional recovery after CTO PCI. Funding Acknowledgement Type of funding source: None

Targeting MEF2 acetylation improves myocardial recovery and overall survival in mice

Abstract Background Post-myocardial infarct remodeling is a complex process that is strongly associated with the eventual development of heart failure, and involves myocyte hypertrophy, specific alterations in gene expression and mitochondrial metabolism, myocyte death, fibrosis, and incursion of inflammatory mediators. Many of these alterations involve dynamic changes in lysine acetylation (KAc), a key regulatory post-transcriptional modification in the nucleus and cytosol, and can be blocked by small molecules with broad activity against histone deacetylases (HDACi). The downstream targets of HDACi and other KAc modulators remain to be established, and the safety of this class of agent for long-term administration in heart failure is similarly unknown. We recently reported that a small molecule probe (8MI) selectively blocking acetylation of transcription factor MEF2 is effective in preventing and reversing pressure overload hypertrophy in vivo, without altering overall histone acetylation. Hypothesis Treatment with a MEF2-selective KAc modulator will accelerate cardiac functional recovery after myocardial infarction. Methods The left coronary artery was permanently ligated (PCO) in 8–10 week C57BL/6J mice; controls underwent thoracotomy only (Sham). Within each group, half received 8MI (20–100mg/kg) by gavage daily, beginning at 30 min, and half received diluent only (DMSO). Treatment was continued for 31 days with weekly echocardiography. Mice from each group (n=3–6) were euthanized weekly for gross and histological analysis. Separately, mice were subjected to transverse aortic banding (TAC) +/− 8MI. Comparative LV RNASeq data were analysed using Gene Set Enrichment Analysis at 4 weeks, and median survival was determined. Results At 24 hours all PCO vs. Sham mice had reduced ejection fraction (62.1±1.08% vs. 80.9±1.08%), increased LV diastolic dimensions, and decreased systolic wall thickening (n =min. 8 per group, p &amp;lt; E-001). Over 4 weeks, heart weights progressively increased in PCO mice together with lung and liver congestion. 8MI dose-dependently improvedeach of these parameters, with near-normal function and organ weights at 4 weeks in higher-dose groups. 8MI also reduced infarct size, compensatory hypertrophy, and fibrosis at 4 weeks. In parallel, 8MI extended median survival by 1.67-fold after TAC (127.5 vs 76 days, p&amp;lt;0.0001, 8MI vs DMSO). RNASeq +GSEA analysis revealed that 8MI treatment blocked MEF2 target gene induction, while enriching for gene sets Oxidative Phosphorylation and Myc Targets (FDR q values 0.000 and 0.041) compared with DMSO. Conclusion An inhibitor of MEF2 acetylation promoted significant functional and pathological recovery in a mouse model of myocardial infarction, associated with suppression of MEF2-dependent transcription. These findings point to a novel approach to preventing myocardial functional decline, and improving survival, after myocardial injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health; Miami Heart Research Institute

Constraint-induced movement therapy promotes motor recovery after neonatal stroke in the absence of neural precursor activation.

Neonatal stroke is a leading cause of long-term disability and currently available rehabilitation treatments are insufficient to promote recovery. Activating neural precursor cells (NPCs) in adult rodents, in combination with rehabilitation, can accelerate functional recovery following stroke. Here, we describe a novel method of constraint-induced movement therapy (CIMT) in a rodent model of neonatal stroke that leads to improved functional outcomes, and we asked whether the recovery was correlated with expansion of NPCs. A hypoxia/ischemia (H/I) injury was induced on postnatal day 8 (PND8) via unilateral carotid artery ligation followed by systemic hypoxia. One week and two weeks post-H/I, CIMT was administered in the form of 3 botulinum toxin (Botox) injections, which induced temporary paralysis in the unaffected limb. Functional recovery was assessed using the foot fault task. NPC proliferation was assessed using the neurosphere assay and EdU immunohistochemistry. We found that neonatal H/I injury alone expands the NPC pool by >2.5-fold relative to controls. We determined that using Botox injections as a method to provide CIMT results in significant functional motor recovery after H/I. However, CIMT does not lead to enhanced NPC activation or migration into the injured parenchyma in vivo. At the time of functional recovery, increased numbers of proliferating inflammatory cells were found within the injured motor cortex. Together, these findings suggest that NPC activation following CIMT does not account for the observed functional improvement and suggests that CIMT-mediated modification of the CNS inflammatory response may play a role in the motor recovery.

The influence of statin withdrawal and adherence on stroke outcomes.

With multiple proven benefits, statin therapy has become the most critical advance in stroke prevention. We aimed to evaluate the risk factors and the effect of poor adherence or statin interruption on the clinical outcomes of ischemic stroke. This prospective cohort study included patients admitted with acute ischemic stroke between 2014 and 2018. Consecutive patients were distinguished into subgroups according to the adherence and withdrawal of statin. All participants were followed for 24months. The outcomes included stroke recurrence, major cardiovascular events, all-cause mortality, and functional performance. Functional outcome was assessed using the modified Rankin Scale at 7days, 30days, 6months, and 2years after hospital admission for ischemic stroke. In a secondary analysis, outcome variables were compared with statin-naïve patients. We included 479 patients with acute ischemic stroke. The mean age was 58.3, and 55.0% were male. There were 96 (21.8%) patients who received no statin, 150 (34.9%) patients with poor adherence, 40 (9.1%) patients with intermediate adherence, and 154 (35.0%) patients with good adherence. There were 54 (15.7%) cases of withdrawal of treatment. Patients with hypertension, previous stroke, and large-artery atherosclerosis were associated with poor adherence (p< 0.05). Those with poor adherence were significantly associated with worse functional outcomes and a higher incidence of stroke recurrence (p< 0.05). Significant functional recovery was just seen in patients with satisfactory adherence. The suboptimal use of statins is associated with significantly worse clinical outcomes in stroke patients.