Spontaneous Functional Recovery Research Articles

Letter to Editor on "Unresolved questions in the recovery of spontaneous erectile function in young men treated with daily tadalafil".

Letter to Editor on "Unresolved questions in the recovery of spontaneous erectile function in young men treated with daily tadalafil".

The expression profile of brain-derived exosomal miRNAs reveals the key molecules responsible for spontaneous motor function recovery in a rat model with permanent middle cerebral artery occlusion.

The analysis of alterations in the expression and functionality of brain-derived exosomal miRNAs within ischemic stroke lesions provides significant insights into the mechanisms that contribute to disease recovery. We assessed spontaneous motor function in a rat model of permanent middle cerebral artery occlusion (pMCAO) using motor function scores and magnetic resonance imaging (MRI). Brain-derived exosomes from the infarcted brain tissue of the animal model were extracted and high-throughput sequencing of them was performed followed by bioinformatics analysis for differentially expressed miRNAs target genes. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure expression levels of differentially expressed miRNAs at various time points. The oxygen-glucose deprivation (OGD) model was established to investigate gene function through the assessment of cell proliferation and apoptosis using EdU proliferation and JC-1 apoptosis assay. The rat model demonstrated a spontaneous recovery of motor function and a reduction in cerebral infarction area from day 1 to day 14 post-operation. Over the course of the recovery period, miR-24-3p, miR-129-1-3p, and miR-212-5p maintained consistent expression levels, reaching their peak on the initial day following surgery. In the cell model, EdU detection indicated that miR-129-1-3p promoted cellular proliferation, while JC-1 detection revealed its suppressive impact on cellular apoptosis. The current research findings indicated the presence of spontaneous motor function restoration in a rat model of ischemic stroke. MiR-24-3p, miR-129-1-3p, and miR-212-5p were identified as pivotal genes in this recovery process, with miR-129-1-3p potentially influencing the restoration of spontaneous motor function in ischemic stroke through the regulation of neuronal proliferation and apoptosis.

Surgical Repair of Obstetric Brachial Plexus Injuries: A Case Series and Discussion of the Current Literature

ObjectiveTo assess factors which may influence surgical success following brachial plexus reconstruction for Obstetric Brachial Plexus Injury (OBPI). MethodsWe retrospectively reviewed the charts of 27 consecutive patients who underwent brachial plexus reconstruction following OBPI by a single pediatric neurosurgeon, 22 of which had adequate follow-up be included in analysis. Data on pre-operative function, intra-operative findings, and post-operative outcomes were collected. Mallet grades for abduction, external rotation, and hand-to-mouth were used as a measure of upper trunk function. ResultsAll patients undergoing brachial plexus reconstruction (n=27) were found to have some degree of upper-trunk injury intra-operatively. Of the 22 patients with adequate follow-up to be included in the analysis, 17 had some degree of improvement in Mallet grade post-operatively. Prior to surgery, 95% (21/22) of patients had an abduction Mallet grade of 1, compared to 23% (5/22) at the time of maximum improvement (p<0.001). These values were 100% (20/20) to 35% (5/14) (p<0.001), and 95% (21/22) to 27% (6/22) (p<0.001) for external rotation and hand-to-mouth, respectively. The average time to maximum Mallet grade was 583 days (SD 356 days). Age at time of surgery and time to maximum recovery were not found to be correlated. ConclusionBrachial plexus reconstruction is an effective treatment modality for patients without spontaneous recovery of upper extremity function following OBPI, although identifying the optimal age-range for surgery remains elusive. Patients with intraoperative findings consistent with a more severe injury may be less likely to benefit from surgery.

ADSCs encapsulated in Gelatin methacrylate substrate promotes the repair of peripheral nerve injury by SIRT6/PGC-1α pathway

Peripheral nerve injury is a prevalent disease but the spontaneous recovery of nerve function is protracted and incomplete. Given the damaging of stem cells and fragile of intra-neural structures in the course of stem cell transplantation, our study tried to investigate whether encapsulating adipose derived mesenchymal stem cells (ADSCs) with GelMA could achieve better repair in peripheral nerve injury. PC-12 cells were cultured on the surface of GelMA encapsulating ADSCs and 3D co-culture system was constructed. CCK-8, Real-Time PCR, ELISA, Immunofluorescent Assay and Western Blot were used to evaluate the functionality of this system. Ultimately, nerve conduit containing the 3D co-culture system was linked between the two ends of an injured nerve. ADSCs encapsulated in 5% GeIMA had a better activity than 10% GeIMA. Furthermore, the viability of PC-12 cells was also better in this 3D co-culture system than in co-culture system with ADSCs without GeIMA. The expression of SIRT6 and PGC-1α in PC-12 cells were prominently promoted, and the entry to nuclear of PGC-1α was more obvious in this 3D co-culture system. After silencing of SIRT6, the protein expression level of PGC-1α was inhibited, and the activity of PC-12 cells was significantly reduced, suggesting that ADSCs encapsulated in GelMA upregulated the expression of SIRT6 to induce the level of PGC-1α protein, thereby achieving an impact on the activity of PC-12 cells. In vivo, nerve conduit containing the 3D co-culture system significantly promoted the repair of damaged peripheral nerves. In conclusion, our study demonstrated that 5% GelMA enhanced ADSCs activity, thereby promoting the activity of nerve cells and repair of damaged peripheral nerves by SIRT6/PGC-1α pathway.

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery.

JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury-Induced Mechanical Pain.

Cypin (cytosolic postsynaptic density protein 95 interactor) is the primary guanine deaminase in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain. Since neuropathic pain is a comorbidity associated with spinal cord injury (SCI), we postulated that small molecule cypin inhibitor B9 treatment could attenuate SCI-induced neuropathic pain, potentially by interfering with UA production. However, we also considered that this treatment could hinder the neuroprotective effects of UA and, in doing so, exacerbate SCI outcomes. To address our hypothesis, we induced a moderate midthoracic contusion SCI in female mice and assessed whether transient intrathecal administration of B9, starting at 1 d postinjury (dpi) until 7 dpi, attenuates mechanical pain in hindlimbs at 3 weeks pi. We also evaluated the effects of B9 on the spontaneous recovery of locomotor function. We found that B9 alleviates mechanical pain but does not affect locomotor function. Importantly, B9 does not exacerbate lesion volume at the epicenter. In accordance with these findings, B9 does not aggravate glutamate-induced excitotoxic death of SC neurons in vitro. Moreover, SCI-induced increased astrocyte reactivity at the glial scar is not altered by B9 treatment. Our data suggest that B9 treatment reduces mechanical pain without exerting major detrimental effects following SCI.

Ballistic injuries of the humerus: A matched cohort analysis

Introduction Ballistic fractures of the humerus secondary to gunshot wounds are increasingly common injuries that pose challenges for orthopedic surgeons. The primary purpose of this study was to examine the rates of neurovascular injury, compartment syndrome, and infection of ballistic humerus fractures relative to blunt, non-penetrating fractures. Methods A consecutive cohort of 135 patients with ballistic humerus fractures and 167 patients with blunt humerus fractures treated at a level 1 trauma center were identified. A review of patient medical records and radiographic studies was performed to obtain demographic information, injury mechanism, fracture location, choice of treatment, and complications. Statistical analysis was performed using independent sample t-tests, chi-square tests, and odds ratios ( p &lt; 0.05 significance). Results Compared with blunt fractures, patients in the ballistic fracture cohort were younger, male, African American, test positive for illicit drug use, and sustain proximal fractures. Ballistic fractures had significantly lower Injury Severity Scores and New Injury Severity Scores. Ballistic fractures were three times as likely to present with neurovascular injury than blunt fractures (OR: 2.927, p &lt; 0.001). The overall rate of spontaneous recovery of significant motor function for ballistic fractures with neurologic injury was 55%. There were no statistically significant differences in rates of vascular injury, compartment syndrome, infection, non-union, or the need for soft tissue reconstruction. Conclusion Compared with blunt humeral fractures, ballistic fractures appear to have a significantly higher rate of neurologic injury but no increased risk for compartment syndrome or infection. Surgical treatment of ballistic humeral injuries was not associated with increased neurological recovery compared to non-operatively managed fractures.

Modified Blair’s (Transparotid) Approach for Open Reduction of Condylar Fractures - Our Experience

The treatment of condylar fractures is complex and controversial.The aim of the present study is to evaluate the treatment outcomes of open reduction of condylar fractures using Modified Blair’s (Transparotid) approach. Materials and Methods: A prospective study was conducted March 2021 to April 2023. Patients reporting to the department with condylar neck/ subcondylar fractures with or without other facial bone fractures and requiring open reduction internal fixation were included in the study. Modified Blair’s (Transparotid) approach was used to expose the condylar fracture site. Intraoperative surgical time of exposure, post-operative variables like swelling, pain, status of occlusion, facial nerve dysfunction, salivary leakage (salivary fistula/sialocele), Frey’s syndrome, greater auricular nerve damage, subjective assessment of scar esthetics were recorded after immediate post-op day 1, after 1st post-op week, after 1st post-op month, after 3rd post-op month and after 6th post-operative month. Results: The study included 36 condylar fractures sites in 30 patients, 24 unilateral and 6 bilateral. The mean average time from incision to exposure of fracture site was 22.5 minutes. Mild occlusal discrepancy was recorded in 3 patients which was corrected with elastic traction in the post-operative period. Transient facial nerve dysfunction was recorded in 6 patients with spontaneous recovery of nerve function within 6 months. No other major complications were noted. Conclusion: The Modified Blairs (transparotid) approach provided sufficient exposure of the condylar fracture site to facilitate anatomical reduction. It is a good technique and provides stable results with low complication rates and acceptable scar.

Spontaneous physical functional recovery after hospitalization for COVID-19: insights from a 1 month follow-up and a model to predict poor trajectory.

Long COVID syndrome has emerged as a new global healthcare challenge, with impaired physical performance being a prominent debilitating factor. Cardiopulmonary rehabilitation is a mainstay of management of symptomatic post-COVID patients, and optimization of candidate selection might allow for more effective use of available resources. In order to study the natural dynamics and to identify predictors of physical functional recovery following hospitalization for COVID-19, 6 min walk test was performed pre-discharge in 176 patients (40% hypertensive, 53% female, mean age 53.2 ± 13.5 years) with re-evaluation at 1 month. Six min walk distance and the reached percent of predicted distance (6MWD%) were suboptimal at both visits-396 ± 71 m (68.7 ± 12.4%) pre-discharge and 466 ± 65 m (81.8 ± 13.6%) at 1 month. Associated changes included significant oxygen desaturation (2.9 ± 2.5 and 2.3 ± 2.2%, respectively) and insufficient increment of heart rate during the test (24.9 ± 17.5 and 28.2 ± 12.0 bpm) that resulted in low reached percent of individual maximum heart rate (61.1 ± 8.1 and 64.3 ± 8.2%). Automatic clusterization of the study cohort by the 6MWD% changes has allowed to identify the subgroup of patients with poor "low base-low increment" trajectory of spontaneous post-discharge recovery that were characterized by younger age (38.2 ± 11.0 vs. 54.9 ± 12.1, p < 0.001) but more extensive pulmonary involvement by CT (43.7 ± 8.8 vs. 29.6 ± 19.4%, p = 0.029) and higher peak ESR values (36.5 ± 9.7 vs. 25.6 ± 12.8, p < 0.001). Predictors of poor recovery in multivariate logistic regression analysis included age, peak ESR, eGFR, percentage of pulmonary involvement by CT, need for in-hospital oxygen supplementation, SpO2 and mMRC dyspnea score pre-discharge, and history of hypertension. COVID-19 survivors were characterized by decreased physical performance pre-discharge as assessed by the 6 min walk test and did not completely restore their functional status after 1 month of spontaneous recovery, with signs of altered blood oxygenation and dysautonomia contributing to the observed changes. Patients with poor "low base-low increment" trajectory of post-discharge recovery were characterized by younger age but more extensive pulmonary involvement and higher peak ESR values. Poor post-discharge recovery in the study cohort was predictable by the means of machine learning-based classification model that used age, history of hypertension, need for oxygen supplementation, and ESR as inputs.

Machine Learning-assisted Quantitative Mapping of Intracortical Axonal Plasticity Following a Focal Cortical Stroke in Rodents.

Stroke destroys neurons and their connections leading to focal neurological deficits. Although limited, many patients exhibit a certain degree of spontaneous functional recovery. Structural remodeling of the intracortical axonal connections is implicated in the reorganization of cortical motor representation maps, which is considered to be an underlying mechanism of the improvement in motor function. Therefore, an accurate assessment of intracortical axonal plasticity would be necessary to develop strategies to facilitate functional recovery following a stroke. The present study developed a machine learning-assisted image analysis tool based on multi-voxel pattern analysis in fMRI imaging. Intracortical axons originating from the rostral forelimb area (RFA) were anterogradely traced using biotinylated dextran amine (BDA) following a photothrombotic stroke in the mouse motor cortex. BDA-traced axons were visualized in tangentially sectioned cortical tissues, digitally marked, and converted to pixelated axon density maps. Application of the machine learning algorithm enabled sensitive comparison of the quantitative differences and the precise spatial mapping of the post-stroke axonal reorganization even in the regions with dense axonal projections. Using this method, we observed a substantial extent of the axonal sprouting from the RFA to the premotor cortex and the peri-infarct region caudal to the RFA. Therefore, the machine learningassisted quantitative axonal mapping developed in this study can be utilized to discover intracortical axonal plasticity that may mediate functional restoration following stroke.

Dynamic alterations of spontaneous neural activity in post-stroke aphasia: a resting-state functional magnetic resonance imaging study.

The dynamic alterations in spontaneous neural activity of the brain during the acute phase of post-stroke aphasia (PSA) remain unclear. Therefore, in this study, dynamic amplitude of low-frequency fluctuation (dALFF) was applied to explore abnormal temporal variability in local functional activity of the brain during acute PSA. Resting-state functional magnetic resonance imaging (rs-fMRI) data from 26 patients with PSA and 25 healthy controls (HCs) were acquired. The sliding window method was used to assess dALFF, with the k-means clustering method used to identify dALFF states. The two-sample t-test was applied to compare differences in dALFF variability and state metrics between the PSA and HC groups. (1) In the PSA group, greater variance of dALFF in the cerebellar network (CBN) and left fronto-temporo-parietal network (FTPN) was observed. (2) Three dALFF states were identified among all subjects. States 1 and 2 were identified in the PSA patients, and the two dALFF states shared a similar proportion. Moreover, the number of transitions between the two dALFF states was higher in the patients compared with that in HCs. The results of this study provide valuable insights into brain dysfunction that occurs during the acute phase (6.00 ± 3.52 days) of PSA. The observed increase in variability of local functional activities in CBN and left FTPN may be related to the spontaneous functional recovery of language during acute PSA, and it also suggests that cerebellum plays an important role in language.

An animal model induced by bilateral cavernous nerve crushing mimics post-radical prostatectomy erectile dysfunction in old rats

AimOver the years, the cavernous nerve (CN) crushing injury rat model has been frequently used for studying post-radical prostatectomy erectile dysfunction (pRP-ED). However, models based on young and healthy rats reportedly exhibit spontaneous recovery of erectile function. Our investigation purpose was to evaluate bilateral CN crushing (BCNC) effects on erectile function besides penile corpus cavernosum pathology in young and old rats and verify whether the BCNC modeling in old rats is more suitable to mimic pRP-ED. Materials and methodsThirty young and old male Sprague-Dawley (SD) rats had been divided into three groups in a random manner: sham-operated group (Sham), CN-injured 2-week group (BCNC-2W), and CN-injured 8-week group (BCNC-8W). At 2 and 8 weeks postoperatively, mean arterial pressure (MAP) along with intracavernosal pressure (ICP) had been determined, respectively. Then, the penis was harvested for histopathological studies. Key findingWe found that young rats exhibited erectile function spontaneous recovery 8 weeks following BCNC, while old ones failed to recover erectile function. After BCNC, the abundance of nNOS-positive nerve and smooth muscle were reduced, whereas apoptotic levels and collagen I content increased. These pathological modifications gradually resumed over time in young rats, unlike in old rats. SignificanceOur findings demonstrate that 18-month-old rats do not spontaneously regain erectile function at 8 weeks after BCNC. Therefore, CN-injury ED modeling in 18-month-old rats may be more suitable for studying pRP-ED.

Correlation between traumatic pelvic ring injuries and sexual dysfunctions: a multicentric retrospective study

PurposeAmong the functional impairments associated with pelvic ring injuries (PRI), sexual dysfunction (SD) is a common clinical issue. The aim of this study is to investigate correlations between traumatic PRI, genitourinary, and sexual dysfunctions, for a proper multidisciplinary treatment.MethodsWe performed an observational, multicentric study, from January 2020 to 2022. We conducted a follow-up after surgery at three, six, 12, and 24 months by measuring the Female Sexual Functioning Index (FSFI), the International Index of Erectile Function (IIEF), the Arizona Sexual Experience Scale (ASEX), the Majeed Score, and the SF-12. Descriptive statistics was conducted on T-test, Whelc’s test, and one-way ANOVA which were performed when appropriate.ResultsA total of 76 patients (mean age 42.17 ± 15 years) were included in the study and allocated into three groups (A, B, and C). Tile A group revealed good sexual outcomes, similar to that of healthy patients. Tile B group demonstrated worsen SD than the previous group. In Tile C group, there was a longer average duration of the orthopaedic surgery when compared to group B. However, in terms of SDs, statistical significance could not be demonstrated between groups C and B.ConclusionsWe observed a progressive spontaneous recovery of sexual function, corresponding to each PRI group. Moreover, men classified as B2 had milder SDs than B1 male patients.

Temporal and Spatial Gene Expression Profile of Stroke Recovery Genes in Mice.

Stroke patients show some degree of spontaneous functional recovery, but this is not sufficient to prevent long-term disability. One promising approach is to characterize the dynamics of stroke recovery genes in the lesion and distant areas. We induced sensorimotor cortex lesions in adult C57BL/6J mice using photothrombosis and performed qPCR on selected brain areas at 14, 28, and 56 days post-stroke (P14-56). Based on the grid walk and rotating beam test, the mice were classified into two groups. The expression of cAMP pathway genes Adora2a, Pde10a, and Drd2, was higher in poor- compared to well-recovered mice in contralesional primary motor cortex (cl-MOp) at P14&56 and cl-thalamus (cl-TH), but lower in cl-striatum (cl-Str) at P14 and cl-primary somatosensory cortex (cl-SSp) at P28. Plasticity and axonal sprouting genes, Lingo1 and BDNF, were decreased in cl-MOp at P14 and cl-Str at P28 and increased in cl-SSp at P28 and cl-Str at P14, respectively. In the cl-TH, Lingo1 was increased, and BDNF decreased at P14. Atrx, also involved in axonal sprouting, was only increased in poor-recovered mice in cl-MOp at P28. The results underline the gene expression dynamics and spatial variability and challenge existing theories of restricted neural plasticity.

Neurovascular Unit Compensation from Adjacent Level May Contribute to Spontaneous Functional Recovery in Experimental Cervical Spondylotic Myelopathy.

The progression and remission of cervical spondylotic myelopathy (CSM) are quite unpredictable due to the ambiguous pathomechanisms. Spontaneous functional recovery (SFR) has been commonly implicated in the natural course of incomplete acute spinal cord injury (SCI), while the evidence and underlying pathomechanisms of neurovascular unit (NVU) compensation involved in SFR remains poorly understood in CSM. In this study, we investigate whether compensatory change of NVU, in particular in the adjacent level of the compressive epicenter, is involved in the natural course of SFR, using an established experimental CSM model. Chronic compression was created by an expandable water-absorbing polyurethane polymer at C5 level. Neurological function was dynamically assessed by BBB scoring and somatosensory evoked potential (SEP) up to 2 months. (Ultra)pathological features of NVUs were presented by histopathological and TEM examination. Quantitative analysis of regional vascular profile area/number (RVPA/RVPN) and neuroglial cells numbers were based on the specific EBA immunoreactivity and neuroglial biomarkers, respectively. Functional integrity of blood spinal cord barrier (BSCB) was detected by Evan blue extravasation test. Although destruction of the NVU, including disruption of the BSCB, neuronal degeneration and axon demyelination, as well as dramatic neuroglia reaction, were found in the compressive epicenter and spontaneous locomotor and sensory function recovery were verified in the modeling rats. In particular, restoration of BSCB permeability and an evident increase in RVPA with wrapping proliferated astrocytic endfeet in gray matter and neuron survival and synaptic plasticity were confirmed in the adjacent level. TEM findings also proved ultrastructural restoration of the NVU. Thus, NVU compensation changes in the adjacent level may be one of the essential pathomechanisms of SFR in CSM, which could be a promising endogenous target for neurorestoration.

Evaluation of the Physical Treatment Success in Patients with Peripheral Nerve Injury Caused by Firearm

Background: All wars bring high incidence of patients with peripheral nerve injuries, and many of today's knowledge about degeneration, regeneration and surgical treatment in this casuistry come from the period of the global world conflict. Such injuries do not endanger life, but the function of the extremities is threatened, which manifests itself in motor and sensory outbursts, as well as negative psychological implications. Objective: The aims of this article were: a) To present the method of monitoring physical treatment in a patient with a peripheral nerve injury; b) To perform a quantitative analysis of nerve lesions caused by firearms (n = 445);; c) To present the effects of physical treatment for this condition;; d) To analyze the time interval from injury to healing (n = 220);; e) Determine the time from injury until the surgery. Results: Anatomical disruption of axons with complete Waler degeneration. The connective tissue network remains intact and the endoneurium can guide the regenerated nerve fibers to their destination. Spontaneous functional recovery can be expected in 12 to 18 months. Clinical evaluation shows a deficit in the innervation area of damaged axons with muscle atrophy and loss of sensitivity. Nerve recovery can be inhibited by scar formations at the site of injury. Complete interruption of the nerve. Functional recovery is not possible without surgical intervention. Paralysis of mm. atrophy, anesthesia and atrophic skin changes are visible. Conclusion: Rehabilitation is a delicate problem and requires long-term treatment and multidisciplinary cooperation, and is carried out in accordance with the principles of peripheral nerve repair. Factors that facilitate successful regeneration are: a) Pre and post-operative physical treatment; b) Younger age; c) Shorter time since injury (&lt;6 months); d) More distal level of the lesion; e) Absence of factors complicating the injury (infection); and f) The first signs of nerve recovery are the return of sweating and pain.

Heterogeneous natural history of Addison's disease: mineralocorticoid deficiency may predominate.

Autoimmune Addison's disease (AAD) is defined as primary adrenal insufficiency due to immune-mediated destruction of the adrenal cortex. This destruction of steroid-producing cells has historically been thought of as an irreversible process, with linear progression from an ACTH-driven compensated phase to overt adrenal insufficiency requiring lifelong glucocorticoid replacement. However, a growing body of evidence suggests that this process may be more heterogeneous than previously thought, with potential for complete or partial recovery of glucocorticoid secretion. Although patients with persistent mineralocorticoid deficiency despite preserved or recovered glucocorticoid function are anecdotally mentioned, few well-documented cases have been reported to date. We present three patients in the United Kingdom who further challenge the long-standing hypothesis that AAD is a progressive, irreversible disease process. We describe one patient with a 4-year history of mineralocorticoid-only Addison's disease, a patient with spontaneous recovery of adrenal function and one patient with clinical features of adrenal insufficiency despite significant residual cortisol function. All three patients show varying degrees of mineralocorticoid deficiency, suggesting that recovery of zona fasciculata function in the adrenal cortex may occur independently to that of the zona glomerulosa. We outline the current evidence for heterogeneity in the natural history of AAD and discuss possible mechanisms for the recovery of adrenal function.

Assessment of hindlimb motor recovery after severe thoracic spinal cord injury in rats: classification of CatWalk XT® gait analysis parameters.

Assessment of locomotion recovery in preclinical studies of experimental spinal cord injury remains challenging. We studied the CatWalk XT® gait analysis for evaluating hindlimb functional recovery in a widely used and clinically relevant thoracic contusion/compression spinal cord injury model in rats. Rats were randomly assigned to either a T9 spinal cord injury or sham laminectomy. Locomotion recovery was assessed using the Basso, Beattie, and Bresnahan open field rating scale and the CatWalk XT® gait analysis. To determine the potential bias from weight changes, corrected hindlimb (H) values (divided by the unaffected forelimb (F) values) were calculated. Six weeks after injury, cyst formation, astrogliosis, and the deposition of chondroitin sulfate glycosaminoglycans were assessed by immunohistochemistry staining. Compared with the baseline, a significant spontaneous recovery could be observed in the CatWalk XT® parameters max intensity, mean intensity, max intensity at%, and max contact mean intensity from 4 weeks after injury onwards. Of note, corrected values (H/F) of CatWalk XT® parameters showed a significantly less vulnerability to the weight changes than absolute values, specifically in static parameters. The corrected CatWalk XT® parameters were positively correlated with the Basso, Beattie, and Bresnahan rating scale scores, cyst formation, the immunointensity of astrogliosis and chondroitin sulfate glycosaminoglycan deposition. The CatWalk XT® gait analysis and especially its static parameters, therefore, seem to be highly useful in assessing spontaneous recovery of hindlimb function after severe thoracic spinal cord injury. Because many CatWalk XT® parameters of the hindlimbs seem to be affected by body weight changes, using their corrected values might be a valuable option to improve this dependency.

Spontaneous Behavioural Recovery Following Stroke Relates to the Integrity of Parietal and Temporal Regions.

Stroke is a devastating disease that results in neurological deficits and represents a leading cause of death and disability worldwide. Following a stroke, there is a degree of spontaneous recovery of function, the neural basis of which is of great interest among clinicians in their efforts to reduce disability following stroke and enhance rehabilitation. Conventionally, work on spontaneous recovery has tended to focus on the neural reorganization of motor cortical regions, with comparably little attention being paid to changes in non-motor regions and how these relate to recovery. Here we show, using structural neuroimaging in a macaque stroke model (N = 31) and by exploiting individual differences in spontaneous behavioural recovery, that the preservation of regions in the parietal and temporal cortices predict animal recovery. To characterize recovery, we performed a clustering analysis using Non-Human Primate Stroke Scale (NHPSS) scores and identified a good versus poor recovery group. By comparing the preservation of brain volumes in the two groups, we found that brain areas in integrity of brain areas in parietal, temporal and somatosensory cortex were associated with better recovery. In addition, a decoding approach performed across all subjects revealed that the preservation of specific brain regions in the parietal, somatosensory and medial frontal cortex predicted recovery. Together, these findings highlight the importance of parietal and temporal regions in spontaneous behavioural recovery.

Maf1 is an intrinsic suppressor against spontaneous neural repair and functional recovery after ischemic stroke

IntroductionSpontaneous recovery after CNS injury is often very limited and incomplete, leaving most stroke patients with permanent disability. Maf1 is known as a key growth suppressor in proliferating cells. However, its role in neuronal cells after stroke remains unclear. ObjectiveWe aimed to investigate the mechanistic role of Maf1 in spontaneous neural repair and evaluated the therapeutic effect of targeting Maf1 on stroke recovery. MethodsWe used mouse primary neurons to determine the signaling mechanism of Maf1, and the cleavage-under-targets-and-tagmentation-sequencing to map the whole-genome promoter binding sites of Maf1 in isolated mature cortical neurons. Photothrombotic stroke model was used to determine the therapeutic effect on neural repair and functional recovery by AAV-mediated Maf1 knockdown. ResultsWe found that Maf1 mediates mTOR signaling to regulate RNA polymerase III (Pol III)-dependent rRNA and tRNA transcription in mouse cortical neurons. mTOR regulates neuronal Maf1 phosphorylation and subcellular localization. Maf1 knockdown significantly increases Pol III transcription, neurite outgrowth and dendritic spine formation in neurons. Conversely, Maf1 overexpression suppresses such activities. In response to photothrombotic stroke in mice, Maf1 expression is increased and accumulates in the nucleus of neurons in the peripheral region of infarcted cortex, which is the key region for neural remodeling and repair during spontaneous recovery. Intriguingly, Maf1 knockdown in the peri-infarct cortex significantly enhances neural plasticity and functional recovery. Mechanistically, Maf1 not only interacts with the promoters and represses Pol III-transcribed genes, but also those of CREB-associated genes that are critical for promoting plasticity during neurodevelopment and neural repair. ConclusionThese findings indicate Maf1 as an intrinsic neural repair suppressor against regenerative capability of mature CNS neurons, and suggest that Maf1 is a potential therapeutic target for enhancing functional recovery after ischemic stroke and other CNS injuries.