Long-term Functional Recovery Research Articles

Evaluation of benefits and risks of immunosuppressive drugs in biomaterial-based neural progenitor cell transplantation for spinal cord injury repair

Spinal cord injury (SCI) can disrupt neural connections and impair locomotion and sensation function. Currently, biomaterials containing neural progenitor cells (NPCs) are widely used to replace damaged tissue or provide support for neural regeneration following SCI. Immunosuppressive drugs (ISDs) are commonly utilized to ensure the survival of transplanted NPC in SCI. However, the potential benefits and risks of using ISDs in NPC transplantation with biomaterials for SCI repair has not been deeply studied. Herein, an orderly aligned collagen sponge scaffold (ACSS) combined with human embryonic spinal cord neural progenitor cells (hscNPCs) was transplanted into SCI rats, with or without ISDs. Results showed that ISDs suppressed cell-mediated immune and inflammatory responses, maintained early survival and differentiation capacity of transplanted cells, and promoted early functional recovery of SCI rats. However, ISDs did not influence endogenous nerve regeneration, angiogenesis, glial scarring or long-term functional recovery after ACSS and hscNPC transplantation. Additionally, ISDs can induce toxicity in multiple organ and impact the survival of animals after SCI. Thus, careful evaluation of the benefits and risks is necessary to maximize therapeutic efficiency when administrating ISD in combination with scaffold-loaded NPCs for SCI repair.

Endothelial peroxiredoxin-4 is indispensable for blood–brain barrier integrity and long-term functional recovery after ischemic stroke

The endothelial lining of cerebral microvessels is damaged relatively early after cerebral ischemia/reperfusion (I/R) injury and mediates blood-brain barrier (BBB) disruption, neurovascular injury, and long-term neurological deficits. I/R induces BBB leakage within 1 h due to subtle structural alterations in endothelial cells (ECs), including reorganization of the actin cytoskeleton and subcellular redistribution of junctional proteins. Herein, we show that the protein peroxiredoxin-4 (Prx4) is an endogenous protectant against endothelial dysfunction and BBB damage in a murine I/R model. We observed a transient upregulation of Prx4 in brain ECs 6 h after I/R in wild-type (WT) mice, whereas tamoxifen-induced, selective knockout of Prx4 from endothelial cells (eKO) mice dramatically raised vulnerability to I/R. Specifically, eKO mice displayed more BBB damage than WT mice within 1 to 24 h after I/R and worse long-term neurological deficits and focal brain atrophy by 35 d. Conversely, endothelium-targeted transgenic (eTG) mice overexpressing Prx4 were resistant to I/R-induced early BBB damage and had better long-term functional outcomes. As demonstrated in cultures of human brain endothelial cells and in animal models of I/R, Prx4 suppresses actin polymerization and stress fiber formation in brain ECs, at least in part by inhibiting phosphorylation/activation of myosin light chain. The latter cascade prevents redistribution of junctional proteins and BBB leakage under conditions of Prx4 repletion. Prx4 also tempers microvascular inflammation and infiltration of destructive neutrophils and proinflammatory macrophages into the brain parenchyma after I/R. Thus, the evidence supports an indispensable role for endothelial Prx4 in safeguarding the BBB and promoting functional recovery after I/R brain injury.

Rehabilitation Techniques Before and After Total Knee Arthroplasty for a Better Quality of Life.

The most important gold standard treatment following advanced knee osteoarthritis is total knee arthroplasty. Following surgery oftotal knee replacement, the majority of patients reportdecreased pain and successful long-term results, but recovery is unpredictable, and most patients continue to exhibit muscle weakness in their lower limbs and functional limitations in comparison to similarly aged control individuals. The goal of this review article was to systematically review different articles containing controlled and randomized studies to find out the effectiveness of outpatient care postoperatively on short- and long-term functional recovery. The purpose of this review article is to investigate the possible advantages of pre- and postoperative rehabilitation as well as the value of exercise regimen recommendations following total knee replacement. The following interventions after total knee arthroplasty are discussed in this review article: preoperative education and exercises, continuous passive movement, strengthening interventions, aquatic therapy, balanced training, tourniquet exposure, use of alignment and implants, role of apps in phonesand different wearable devices, influence of postoperative protocols, knee bracing, neuromuscular electrical stimulation, and clinical environment.Strengthening and intense functional exercises for patients above 45 years of age,in landor water programs like aquatic activities, with the increasing intensity of the exercisesin accordance with the patient's progress, should be included in the best outpatient physical therapy protocols. Because these exercises are so precisely personalized, the best long-term effects after surgery may come from outpatient physiotherapy performed in a clinical setting under the supervision of a registered physiotherapist or medical professional. This review article also includes the change in the quality and well-being of a patient's lifewho has undergone total knee arthroplasty and practiced the rehabilitation techniques.

Exercise preference in stroke survivors: a concept analysis.

Exercise preference in stroke survivors is related to their adherence to long-term rehabilitation regimen and functional recovery. Although explored recently, the term exercise preference still lacks a clear definition. The aim of this study is to conceptualize exercise preference in stroke survivors. The Walker and Avant method was applied as a framework for the conceptual analysis of exercise preference. Data from 34 publications were collected using seven databases (PubMed, Web of Science, Embase, CINAHL, CNKI, Wanfang Data, and CBM) and applied in the analysis. The search period was from the inception of the database to April 30, 2023. Exercise preference in stroke survivors was defined according to four attributes: priority of choice, behavioral tendency, affective priming, and patience in adherence. The common antecedents of the concept of exercise preference in stroke survivors were classified into patient-related, therapy-related, and environmental-related categories and the consequences were classified into three categories: patient-related, rehabilitation provider-related, and rehabilitation service system-related. Exercise preference in stroke survivors refers to the patient's choice, tendency, affective response, and attitude toward engagement in the recommended rehabilitation regimen. It is beneficial for understanding the essential attributes of exercise preference in stroke survivors by clarifying the concept. In addition, it will facilitate the development of instruments for assessing exercise preference in stroke survivors and the construction of theory-based intervention programs that can improve adherence to exercise rehabilitation.

The presence of anhedonia in individuals with subacute and chronic stroke: an exploratory cohort study.

Anhedonia refers to the diminished capacity to experience pleasure. It has been described both as a symptom of depression and an enduring behavioral trait that contributes its development. Specifically, in stroke patients, anhedonia has been closely linked to depression, resulting in reduced sensitivity to everyday pleasures and intrinsic motivation to engage in rehabilitation programs and maintain a healthy active lifestyle. This condition may hinder patients' recovery, diminishing their autonomy, functioning, and quality of life. We aimed to explore the prevalence and level of anhedonia and those variables that might be associated in patients with both ischemic and hemorrhagic stroke at subacute and chronic phases of the disease. We conducted an exploratory cohort study with a sample of 125 patients with subacute and chronic stroke presenting upper-limb motor deficits. We measured participants' level of anhedonia with four items from the Beck Depression Inventory-II that describe the symptoms of this condition: loss of pleasure, loss of interest, loss of energy, and loss of interest in sex. We also collected demographic and clinical information and evaluated motor and cognitive functions as well as levels of depression, apathy, and various mood states. The results were compared to a sample of 71 healthy participants of similar age, sex, and level of education. Stroke patients demonstrated a significantly higher prevalence (18.5-19.7%) and level of anhedonia compared to the healthy controls (4.3%), regardless of stroke phase, level of motor impairment, and other clinical variables. Furthermore, post-stroke anhedonia was associated with lower levels of motivation and higher levels of negative mood states such as fatigue and anger in the long term. Importantly, anhedonia level was superior in stroke patients than in healthy controls while controlling for confounding effects of related emotional conditions. This study provides novel evidence on the prevalence, level and factors related to anhedonia post-stroke. We emphasize the importance of assessing and treating anhedonia in this population, as well as conducting large-scale cohort and longitudinal studies to test its influence on long-term functional and emotional recovery.

Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain.

Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777 spots, allowing us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of ischemia-associated gene expression in the peri-infarct area of the ischemic hemisphere. Analysis of ligand-receptor interactions in cell communication revealed galectin-9 to cell-surface glycoprotein CD44 (LGALS9-CD44) as a critical signaling pathway after ischemic injury and identified microglia and macrophages as the main source of galectins after stroke. Extracellular vesicle-mediated Lgals9 delivery improved the long-term functional recovery in photothrombotic stroke mice. Knockdown of Cd44 partially reversed these therapeutic effects, inhibiting oligodendrocyte differentiation and remyelination. In summary, our study provides a detailed molecular and cellular characterization of the peri-infact area in a murine stroke model and revealed Lgals9 as potential treatment target that warrants further investigation.

Mitochondria-targeted cerium vanadate nanozyme suppressed hypoxia-ischemia injury in neonatal mice via intranasal administration

Oxidative stress is a major obstacle for neurological functional recovery after hypoxia-ischemia (HI) brain damage. Nanozymes with robust anti-oxidative stress properties offer a therapeutic option for HI injury. However, insufficiency of nanozyme accumulation in the HI brain by noninvasive administration hinders their application. Herein, we reported a cerium vanadate (CeVO4) nanozyme to realize a noninvasive therapy for HI brain in neonatal mice by targeting brain neuron mitochondria. CeVO4 nanozyme with superoxide dismutase activity mainly co-located with neuronal mitochondria 1 h after administration. Pre- and post-HI administrations of CeVO4 nanozyme were able to attenuate acute brain injury, by inhibiting caspase-3 activation, microglia activation, and proinflammation cytokine production in the lesioned cortex 2 d after HI injury. Moreover, CeVO4 nanozyme administration led to short- and long-term functional recovery following HI insult without any potential toxicities in peripheral organs of mice even after prolonged delivery for 4 weeks. These beneficial effects of CeVO4 nanozyme were associated with suppressed oxidative stress and up-regulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression. Finally, we found that Nrf2 inhibition with ML385 abolished the protective effects of CeVO4 nanozyme on HI injury. Collectively, this strategy may provide an applicative perspective for CeVO4 nanozyme therapy in HI brain damage via noninvasive delivery.

Polydopamine-Cloaked Nanoarchitectonics of Prussian Blue Nanoparticles Promote Functional Recovery in Neonatal and Adult Ischemic Stroke Models.

Ischemic stroke is a devastating disease and one of the leading causes of mortality worldwide. Overproduction of reactive oxygen species and inflammatory response contribute to secondary damage following ischemic insult. Nanozymes with robust anti-oxidative stress properties possess therapeutic possibility for ischemic insult. However, insufficiency of nanozyme accumulation in the neuronal mitochondria hindered their application. Herein, we constructed polydopamine-coated Prussian blue nanoparticles (PB@PDA NPs) to realize the targeting neuronal mitochondria for ischemic stroke, with the properties of antioxidant and anti-inflammation. After administration, much higher accumulation of PB@PDA NPs in the brain was observed compared to that in the PB NP group. Moreover, PB@PDA NPs effectively attenuated brain infarct than that of PB NPs in neonatal mice following hypoxia-ischemia (HI) insult. PB@PDA NPs mainly colocated with neuronal mitochondria invivo and invitro. Apart from attenuating oxidative stress, PB@PDA NPs also suppressed neuronal apoptosis and counteracted inflammation, which effectively promote a short- and long-term functional recovery in HI mice. Further, the therapeutic efficacy of PB@PDA NPs was also found in adult ischemic mice via tail vein injection. Collectively, these findings illustrate that PB@PDA NPs via system injection accumulate in neuronal mitochondria and are beneficial for ischemic stroke.

Viral airway injury promotes cell engraftment in an in vitro model of cystic fibrosis cell therapy.

Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well-differentiated CF ALI cultures and delivering non-CF cells at the time of peak injury. Engraftment efficiency was quantified by measuring chimerism by droplet digital PCR and functional ion transport in Ussing chambers. Using this model, we found that human bronchial epithelial cells (HBECs) engraft more efficiently when they are cultured by conditionally reprogrammed cell (CRC) culture methods. Cell engraftment into the airway epithelium requires airway injury, but the extent of injury needed is unknown. We compared three injury models and determined that severe injury with partial epithelial denudation facilitates long-term cell engraftment and functional CFTR recovery up to 20% of wildtype function. The airway epithelium promptly regenerates in response to injury, creating competition for space and posing a barrier to effective engraftment. We examined competition dynamics by time-lapse confocal imaging and found that delivered cells accelerate airway regeneration by incorporating into the epithelium. Irradiating the repairing epithelium granted engrafting cells a competitive advantage by diminishing resident stem cell proliferation. Intentionally, causing severe injury to the lungs of people with CF would be dangerous. However, naturally occurring events like viral infection can induce similar epithelial damage with patches of denuded epithelium. We found that viral preconditioning promoted effective engraftment of cells primed for viral resistance.NEW & NOTEWORTHY Cell therapy is a potential treatment for cystic fibrosis (CF). Here, we model cell engraftment by injuring CF air-liquid interface cultures and delivering non-CF cells. Successful engraftment required severe epithelial injury. Intentionally injuring the lungs to this extent would be dangerous. However, naturally occurring events like viral infection induce similar epithelial damage. We found that viral preconditioning promoted the engraftment of cells primed for viral resistance leading to CFTR functional recovery to 20% of the wildtype.

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

Effects of <i>Ficus Platyphylla</i>-Induced Hypothermia on Long-term Functional Recovery after Ischaemic Stroke

A stroke is a cerebrovascular disease that results from a blockage in the blood supply to part of the brain or a burst blood vessel in the brain. It is the second leading cause of death worldwide, with an annual mortality rate of about 5.5 million. Antithrombotic therapies have failed to provide a cure for this debilitating cerebrovascular disorder, and hypothermia is gaining interest as a novel strategy for the management of stroke. In this study, we evaluated the effects of <em>Ficus platyphylla</em>-induced hypothermia on long-term functional recovery after ischaemic stroke. Histomorphological analysis of the brain demonstrated pathological alterations in the ipsilateral hemisphere of all animals. Animals treated before or immediately after permanent occlusion of the middle cerebral artery (MCAO) had significantly smaller infarct sizes than those given saline. Surgery and treatment did not affect locomotor activity. There were no significant differences between the groups of mice in terms of parameters associated with situational anxiety, including the number of arm changes and percentile time spent on open arms. There were no significant differences between groups regarding the number of buried marbles and sociability. Surgery and treatment did not affect social recognition, but a significant interaction between surgery and treatment was observed. The time mice remained on the rota rod was relatively similar for all groups tested, with no significant differences related to surgery and treatment, nor was there any surgery/treatment interaction. A learning effect represented by a decrease in exploratory activity was observed irrespective of surgery and treatment, and there was no surgery/treatment interaction. The results suggest that <em>Ficus platyphylla</em>-induced hypothermia could be beneficial to long-term functional recovery after ischaemic stroke.

Predictive values of stress hyperglycaemia and glycosylated haemoglobin on admission for long-term recovery of cardiac function in patients with acute myocardial infarction after primary percutaneous coronary intervention.

We aimed to explore the predictive values of stress hyperglycaemia (SHG) and glycosylated haemoglobin (HbA1c) levels on admission for long-term recovery of cardiac function in patients with acute myocardial infarction (AMI) after primary percutaneous coronary intervention (PPCI). A total of 210 AMI patients were randomly selected. The levels of SHG and HbA1c were measured on admission, and all patients were treated with PPCI and followed up for one year. According to the recovery status of cardiac function during follow up, the patients were divided into a good recovery group and a poor recovery group. At one year after treatment, there were statistically significant differences in the levels of SHG (6.75 ± 0.69 vs 7.81 ± 0.92 mmol/l) and HbA1c (5.13 ± 0.25 vs 5.91 ± 0.39%) between the good and poor recovery groups (p < 0.05). The levels of SHG and HbA1c were associated with long-term recovery of cardiac function (p < 0.05). The receiver operating characteristic curves were plotted, and the area under the curves of SHG and HbA1c for predicting the long-term recovery of cardiac function were > 0.70. The levels of SHG and HbA1c were closely associated with longterm recovery of cardiac function after PPCI in AMI patients, displaying high predictive values.

Trajectories of social function in patients with first-episode schizophrenia: Analysis of data from a 10-year follow-up study

BackgroundPatients with schizophrenia may have diverse functional outcomes. However, the long-term functional trajectories of patients with first-episode schizophrenia (FES) are unclear. MethodsWe extracted data from the Chinese First-Episode Schizophrenia Trial, a 10-year prospective study of antipsychotic-naïve patients with FES. We applied K means cluster modelling to longitudinal data on the social function of patients with FES and examined associations of the empirically derived trajectories with baseline clinical characteristics of the 10-year follow-up. OutcomesThree distinct functional trajectories emerged: improving-favorable (39·3%), improving-poor (17·8%) and improving-stable (42·9%). All three trajectories demonstrated Personal and Social Performance (PSP) score improvement in the first six months. The improving-poor trajectory demonstrated PSP score decline during the second six months and thereafter, while PSP scores in the other two trajectories were mainly stable during the same period. Patients in the improving-favorable trajectory had higher baseline PSP scores than those in the improving-poor trajectory (OR=0·904 [0·852, 0·961], p < 0·05) and the improving-stable trajectory (OR=0·870 [0·825, 0·918], p < 0·001) and were more likely to be female than those in the improving-stable trajectory (OR=2·699 [1·030, 7·074], p < 0·05). ConclusionsPatients with FES demonstrated varied long-term functional recovery profiles. The first year, especially the second half of the first year, is a key period for social function interventions that improve long-term functional outcomes. Male patients and patients with poor baseline function may particularly benefit from such interventions.

Glyceryl triacetate promotes blood–brain barrier recovery after ischemic stroke through lipogenesis-mediated IL-33 in mice

BackgroundLipid metabolism has a crucial role in neural repair in neurodegenerative diseases. We recently revealed that lipogenesis-mediated interleukin-33 (IL-33) upregulation lead to blood–brain barrier (BBB) repair after ischemic stroke. However, manipulating the key enzyme fatty acid synthase (FASN) to enhance lipogenesis was very challenging. Glyceryl triacetate (GTA) was used as a donor of acetate and precursor of acetyl coenzyme A, the key substrate for de novo lipogenesis catalyzed by FASN. Therefore, we hypothesized that GTA would promote lipogenesis the peri-infarct after ischemic stroke and contribute to the BBB repair through IL-33.MethodsMiddle cerebral artery occlusion (MCAO) was performed on C57BL mice and GTA was gavage administrated (4 g/kg) on day 2 and 4 after MCAO. Lipogenesis was evaluated by assessment of the protein level of FASN, lipid droplets, and fatty acid products through liquid chromatography-mass spectrometry in the peri-infarct area on day 3 after MCAO, respectively. BBB permeability was determined by extravasation of Evans blue, IgG and dextran, and levels of tight junction proteins in the peri-infarct area on day 7 after MCAO, respectively. Infarct size and neurological defects were assessed on day 7 after MCAO. Brain atrophy on day 30 and long-term sensorimotor abilities after MCAO were analyzed as well. The inhibitor of FASN, C75 and the virus-delivered FASN shRNA were used to evaluate the role of FASN-driven lipogenesis in GTA-improved BBB repair. Finally, the therapeutic potential of recombinant IL-33 on BBB repair and neurological recovery was evaluated.ResultsWe found that treatment with GTA increased the lipogenesis as evidenced by lipid droplets level and lauric acid content, but not the FASN protein level. Treatment with GTA increased the IL-33 level in the peri-infarct area and decreased the BBB permeability after MCAO. However, infarct size and neurological defect score were unchanged on day 7 after MCAO, while the long-term recovery of sensorimotor function and brain atrophy were improved by GTA. Inhibition of lipogenesis using C75 or FASN shRNA reversed the beneficial effect of GTA. Finally, exogenous IL-33 improved BBB repair and long-term functional recovery after stroke.ConclusionCollectively, we concluded that treatment with GTA improved the BBB repair and functional recovery after ischemic stroke, probably by the enhancement of lipogenesis and IL-33 expression.Graphical

Abstract 17851: Prevalence and Predictors of Early Left Ventricular Functional Recovery After Transcatheter Aortic Valve Implantation: The TAVI-NOR Study

Introduction: Pre-intervention left ventricular (LV) ejection fraction (LVEF) in aortic stenosis (AS) patients has prognostic value. However, the hemodynamic changes early after TAVI (transcatheter aortic valve implantation) is not fully explored. Hypothesis: To what extent early functional recovery by a clinically significant increase (≥10%) in LVEF is achievable following TAVI, how it differs from baseline patient characteristics, and its potential prognostic impact. Methods: Between 2012 and 2019, 600 consecutive patients (age 81±6years, 49.3% females) with clinically significant AS underwent TAVI. Echocardiography was performed before and within 8 weeks after TAVI. Variables associated with &lt;10% LVEF improvement were identified. End-points were ≥10% LVEF improvement and all-cause mortality. Results: From baseline to follow-up; 28% of patients achieved ≥10% LVEF improvement. A ≥10% LVEF improvement was observed in 25% of patients with normal baseline flow (indexed stroke volume ≥35ml/m 2 ) versus 38% in low-flow (p=0.002). Impaired kidney function, higher blood pressure (BP), higher baseline LVEF and indexed stroke volume, and lower LV mass was more likely in patients with &lt;10% LVEF. In a multivariate logistic regression analysis, higher baseline systolic BP (OR 1.02; 95% CI 1.01-1.03, p=0.004) and lower LV mass (OR 1.25; 95% CI 1.02-1.54, p=0.031), and new pacemaker implantation (OR 1.55; 95% CI 0.99-2.42, p=0.055) were associated with a higher risk, and baseline LVEF &lt;50% with a lower risk (OR: 0.15; 95% CI: 0.09-0.25) for &lt;10% LVEF improvement following TAVI, independent of CKD, baseline troponin T and NT-proBNP. In a univariate Cox regression model, &lt;10% increase in LVEF in early phase after TAVI was not a significant predictor of mortality (HR 1.16; 95% CI 0.90-1.50, p=0.258). Conclusions: Clinically significant early LV functional recovery was evident in nearly one-third of severe AS patients, especially patients with reduced LVEF and more symptoms at baseline. Higher systolic BP, lower LV mass, and the need for new permanent pacemaker, were independently associated with a higher risk of not achieving early LV function recovery after TAVI. In long-term follow-up early LV functional recovery was not associated with all-cause mortality.

Surgical Treatments for Femoral Shaft Fractures: A Narrative Review.

Femoral shaft fractures are increasingly common due to various traumatic injuries. Intramedullary nail (IMN) is considered the gold standard treatment for these fractures, but comorbidities often require thorough trauma life support and intensive care. The primary goal of treatment is rigid fixation, early mobilisation, and long-term functional recovery. This article reviews current concepts in the treatment of femoral shaft fractures, including the effects of early or delayed operation, differences between antegrade or retrograde intramedullary nailing, alternative methods to using a fracture table, methods to predict nail length before operation, assessing femoral rotation during an operation, and complications.

ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood–brain barrier integrity after traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI.MethodsWe employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood–brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests.ResultsThe activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI.ConclusionASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

Enhanced Gait Recovery in Chronic Post-COVID-19 Stroke: The Role of Combined Physical Rehabilitation

Background: Rehabilitation programs applied in cases of COVID-19-related stroke should counteract not only the effects of the stroke but also the effects of long-term COVID-19. As the molecular processes underlying these cases are still not fully understood, and evidence-based clinical outcomes are scarcely documented, there is a valid need to gather information and develop rehabilitation strategies for these patients. The risks, already clarified in the case of stroke, need to be assessed taking into account the coincidence of the two diseases. Endothelial injuries and emboli that develop after the hypercoagulable state of COVID-19 may take longer to heal, and complications may occur during exercise. This case study attempts to determine what the rehabilitation of a COVID-19-related stroke patient should include. The participant was a 64-year-old male with ischemic right middle cerebral artery stroke, left-side hemiplegia, and middle cerebral artery stenosis, and the CT showed a well-defined area of hypoattenuation in the basal ganglia territory involving the right lentiform nucleus, the anterior and posterior limbs of the internal capsule, and the dorsal part of the external capsule. His NIHSS score was 14, and he registered 15 points on the Barthel index. The patient had a COVID-19 infection two weeks before the stroke event. Methods: Conventional physical therapy was combined with adaptive ballistic strength training, a high-intensity interval training regimen, and manual treatment for myofascial release throughout the chronic recovery phase. Our primary goals were gait rehabilitation, muscle strengthening, weakness management, as well as spasticity reduction, while three different rehabilitation approaches were adopted in a single rehabilitation program to improve the outcome and long-term functional recovery of the patient. Results: The patient progressed in almost every aspect of the assessment criteria. This combined approach’s main success was improved gait speed, gait quality, and improved cardiovascular fitness. Take-away message: In the case of a stroke caused by COVID-19, where the endothelium cells are compromised, HIIT may be questionable due to the poor vascular condition. Based on our results, the low-volume HIIT approach proved appropriate and effective.

Topical electrostimulation for correction of respiratory disorders in spinal cord injury: A review

BACKGROUND: A spinal cord injury can lead to paralysis of the respiratory muscles, resulting in a significant reduction in breathing ability. People with a spinal cord injury face an increased risk of developing various respiratory complications. To date, existing effective technologies positively affect the long-term recovery of respiratory function and create conditions for neuroplasticity in the injured spinal cord. The high relevance and lack of systematization of these techniques in the world literature served as the basis for describing a topical approach in electrostimulation for the correction of respiratory disorders in patients with traumatic spinal cord injuries.&#x0D; AIM: To formulate an algorithm for topical electrostimulation of the spinal cord and respiratory muscles to correct respiratory dysfunction in patients with spinal cord injury based on the latest scientific literature.&#x0D; MATERIALS AND METHODS: This article presents the results of the analysis of peer-reviewed articles that investigated the effects of various electrostimulation techniques on respiratory function in patients with spinal cord injury. Searches were performed on ScienceDirect, Google Scholar, and PubMed for the period from 2000 to 2022.&#x0D; RESULTS: A spinal cord and muscle electrostimulation algorithm was formulated to personalize the treatment approach for patients with spinal cord injury depending on the level and period of traumatic spinal cord injury.&#x0D; CONCLUSIONS: Electrostimulation techniques were found to be effective in the treatment of spinal cord injuries, particularly for the correction of respiratory disorders. The choice of the appropriate neurostimulation technique depends on the severity, injury level, and period of injury. Noninvasive techniques, such as FES and TSSM, can be used from the acute period to the chronic period, whereas invasive techniques, such as epidural stimulation and respiratory pacemaker placement, are appropriate in the chronic period. Despite the positive results of these techniques, further research is needed to develop effective treatment plans and improve their effectiveness and long-term outcomes.

Prediction of Changes in Functional Outcomes During the First Year After Inpatient Stroke Rehabilitation: A Longitudinal Study

ObjectiveTo identify meaningful changes in patients in 3 functional domains (basic mobility [BM], daily activity [DA], and applied cognition [AC]) after discharge from inpatient stroke rehabilitation and to identify the predictors of 1-year functional improvement. DesignA longitudinal, multicenter, prospective cohort study. SettingThe acute care wards of 3 hospitals in the Greater Taipei area of Taiwan. ParticipantsFive hundred patients with stroke in acute care wards (mean age=60±12.2 years, 62% men, N=500). InterventionsNot applicable. Main Outcome Measure(s)The Mandarin version of the Activity Measure for Post-Acute Care (AM-PAC) short forms were assessed at discharge and 3-, 6-, and 12-month follow-up. The minimal detectable change (MDC) was used to categorize changes in the scores as improved and unimproved at the 4 time points. ResultsThe mean scores of the AM-PAC BM and DA subscales substantially increased over the first 3 months after discharge (86% of participants exhibited improvement) and slightly increased during the subsequent 9 months (5∼26% of participants exhibited improvement). However, the mean score of the AC subscale decreased within the first 3 months and increased over the subsequent 9 months (22-23% of participants exhibited improvement). The BM, AC scores at discharge were the dominant predictors of subsequent functional improvement (P<.05). Patients with a higher functional stage at discharge were more likely to experience significant improvement. ConclusionThis study established the capacity of the AM-PAC to predict functional improvement in 3 domains during the early, middle, and late stages of recovery. The findings can assist clinicians in identifying patients at risk of unfavorable long-term functional recovery and providing such patients with tailored interventions during the early stage of rehabilitation.