Neuronal repair after spinal cord injury by in vivo astrocyte reprogramming mediated by the overexpression of NeuroD1 and Neurogenin-2.

BACKGROUND: As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. METHODS: A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-ß (TGF-ß) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). RESULTS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p < 0.0001). Immunofluorescence staining identified astrocytes with neuroblasts and immature neurons cell properties at the site of injury while neuronal marker-specific staining revealed an increased number of mature astrocytes at the injury site. Behavioral assessments showed that the intervention did not improve The BMS (Basso mouse scale) score (p = 0.0726) and gait (p > 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p < 0.0001) and a significant improvement in glial scar proliferation. Electrophysiological assessments revealed a significant improvement in spinal nerve conduction (p < 0.0001) while immunostaining revealed that the levels of TGF-ß protein at the site of injury in the intervention group were lower than control group (p = 0.0034); in addition, P70 s6 and PP2A related to the TGF-ß pathway showed ascending trend (p = 0.0036, p = 0.0152 respectively). CONCLUSIONS: The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord after spinal cord injury can reprogram astrocytes into neurons and significantly enhance cell regeneration at the injury site. The reprogramming of astrocytes can lead to tissue repair, thus improving the reduced threshold and increasing voluntary movements. This strategy can also improve the integrity of the blood-spinal cord barrier and enhance nerve conduction function. However, the simple reprogramming of astrocytes cannot lead to significant improvements in the striding function of the lower limbs.

Acute non-traffic traumatic spinal cord injury in the aging population: Analysis of the National Inpatient Sample 2005-2018.

BACKGROUND: This study aimed to determine risk factors for poor in-hospital outcomes in a large cohort of older adult patients with acute non-traffic traumatic spinal cord injury (tSCI). METHODS: This is a population-based, retrospective, observational study. Data of older adults ≥65 years with a primary discharge diagnosis of acute non-traffic tSCI were extracted from the US National Inpatient Sample (NIS) database 2005-2018. Traffic-related tSCI admissions or patients lacking complete data on age, sex and outcomes of interest were excluded. Univariate and multivariate logistic regression analysis was used to determine associations between variables and in-hospital outcomes. RESULTS: Data of 49,449 older patients (representing 246,939 persons in the US) were analyzed. The mean age was 79.9 years. Multivariable analyses revealed that severe International Classification of Disease (ICD)-based injury severity score (ICISS) (adjusted odds ratio [aOR] = 3.14, 95% confidence interval [CI]: 2.77-3.57), quadriplegia (aOR = 2.79, 95%CI: 2.34-3.32), paraplegia (aOR = 2.60, 95%CI:1.89-3.58), cervical injury with vertebral fracture (aOR = 2.19, 95%CI: 1.90-2.52), and severe liver disease (aOR = 2.33, 95%CI: 1.34-4.04) were all strong independent predictors of in-hospital mortality. In addition, malnutrition (aOR = 3.19, 95% CI: 2.93-3.48) was the strongest predictors of prolonged length of stay (LOS). CONCLUSIONS: Several critical factors for in-hospital mortality, unfavorable discharge, and prolonged LOS among US older adults with acute non-traffic tSCI were identified. In addition to the factors associated with initial severity, the presence of severe liver disease and malnutrition emerged as strong predictors of unfavorable outcomes, highlighting the need for special attention for these patient subgroups.

Elevated IL-23 in skin promotes IL-23 derived Th17 responses in leprosy patients.

Leprosy is an infectious disease caused by non-cultivable bacteria Mycobacterium leprae. Th17 cells play vital roles during pathogenesis of leprosy reactions and IL-23 is involved in Th17 cell differentiation. Although previous studies have reported the participation of IL-23 in leprosy patients in peripheral blood, the role of this cytokine in skin has not yet been described for the disease. In this study, we first evaluated IL-23 expression in the skin of patients with leprosy. Data showed that in keratinocytes, endothelial cells, and macrophages, IL-23 expression was markedly higher in patients compared to that in the normal skin controls. Also, leprosy patients presented higher percentage of IL-17A-producing IL-23R + CD4 T cells than healthy donors. IL-23R blocking induced markedly downregulated IL-17A secretion in leprosy patients but not in healthy donors. Furthermore, TGF-ß expression was significantly elevated after IL-23R blocking. Overall, this study establishes that Th17 cells produce IL-17A in an IL-23 dependent manner in the skin of leprosy patients and provides more focused treatment strategies for Mycobacterium leprae.

Internal Migration and Leprosy in Shanghai from 2000 to 2019: an Epidemiological Study of New Cases.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Massive internal migration from rural to urban areas poses new challenges for leprosy control in Shanghai, China. This retrospective epidemiological study examined new cases of leprosy diagnosed in Shanghai from 2000 to 2019, with emphasis on internal migration cases. There were 145 cases of leprosy in the study period; the majority of cases (89.0%) were internal migrants. Migrant cases had a mean of 25.4 months lag time from onset of symptoms to diagnosis, which was significantly longer than that of resident cases (mean 10.8 months, p < 0.001). Greater lag time from the first visit to diagnosis was observed in migrant cases (mean 23.2 months) compared with resident cases (mean 9.4 months, p < 0.001). A large majority of cases (91.0%) had been misdiagnosed. Internal migrant cases were responsible for most incidences of leprosy in Shanghai. They often did not receive timely diagnosis and treatment, which may have an adverse impact on the prevention of epidemic leprosy.

Utility of the ability for basic movement scale II as a prediction method of ambulation ability in patients after the hip fracture surgery.

BACKGROUND: This study was to investigate whether the Ability for Basic Movement Scale II (ABMS II) at admission of the convalescent rehabilitation ward (CRW) could predict the ambulation ability in patients after hip fracture surgery. METHODS: The data of the ABMS II and Functional Ambulation Category (FAC) of 118 postsurgical patients with hip fracture who were transferred to the CRW were retrospectively analyzed (mean age 82.7 ± 7.9, female/male: 89/29). Binary logistic regression analysis and receiver operating characteristic (ROC) analysis were used to investigate the predictive value of ABMS II for walking ability at discharge. RESULTS: Spearman's correlation analysis showed that there were significantly positive correlations between the ABMS II score at admission and FAC score at discharge (ρ = 0.70, P < 0.05). Logistic regression analysis showed that ABMS II and BMI can be the predictor in both FAC <4 or ≥4 groups. ROC analysis indicated that an optimal cutoff of 24.5 points of ABMS II score predicted independent walking ability (area under the Curve (AUC) 0.87, P < 0.05). CONCLUSIONS: The ABMS II at admission in CRW can be a prediction method of ambulation recovery for the patients after hip fracture surgery. STUDY DESIGN: Retrospective clinical study.

Mechanical stress regulates autophagic flux to affect apoptosis after spinal cord injury.

Increased mechanical stress after spinal cord injury (SCI) expands the scope of nerve tissue damage and exacerbates nerve function defects. Surgical decompression after SCI is a conventional therapeutic strategy and has been proven to have neuroprotective effects. However, the mechanisms of the interaction between mechanical stress and neurons are currently unknown. In this study, we monitored intramedullary pressure (IMP) and investigated the therapeutic benefit of decompression (including durotomy and piotomy) after injury and its underlying mechanisms in SCI. We found that decreased IMP promotes the generation and degradation of LC3 II, promotes the degradation of p62 and enhances autophagic flux to alleviate apoptosis. The lysosomal dysfunction was reduced after decompression. Piotomy was better than durotomy for the histological repair of spinal cord tissue after SCI. However, the autophagy-lysosomal pathway inhibitor chloroquine (CQ) partially reversed the apoptosis inhibition caused by piotomy after SCI, and the structural damage was also aggravated after CQ administration. An antibody microarray analysis showed that decompression may reverse the up-regulated abundance of p-PI3K, p-AKT and p-mTOR caused by SCI. Our findings may contribute to a better understanding of the mechanism of decompression and the effects of mechanical stress on autophagy after SCI.

Ultrasonography of Diaphragm Can Predict Pulmonary Function in Spinal Cord Injury Patients: A Pilot Case-Control Study.

BACKGROUND Ultrasonography of the diaphragm is an under-utilized instrument in cervical spinal cord injury patients. We conducted a pilot study to first compare the difference of diaphragm thickness and the excursion between patients with cervical spinal cord injury and healthy volunteers, and second to correlate diaphragmic ultrasonography and pulmonary function in cervical spinal cord injury patients. MATERIAL AND METHODS Thirty patients with C4-C5 cervical spinal cord injury of more than 1 year and thirty healthy volunteers were included in this study. All demographic data were evaluated. All participants underwent diaphragmic ultrasonography evaluation and pulmonary function test. Diaphragm thickness of both sides and diaphragm excursions of the right hemi-diaphragm were obtained at the end of quiet tidal breathing and maximal inspiration. We compared diaphragmatic thickness and excursions, and we analyzed the relationship between diaphragmatic ultrasonography and pulmonary function. RESULTS All spinal cord injury patients had restrictive pulmonary dysfunction compared to the control group of healthy volunteers. Diaphragm thickness on both sides was significantly increased in spinal cord injury patients. Diaphragmatic excursion in spinal cord injury patients was increased on the right hemi-diaphragm during tidal breathing. However, the right hemi-diaphragmatic excursion was no difference in both groups during maximal inspiration. Right hemi-diaphragmatic excursion during deep breathing correlated positively with expiratory volume in 1 second (P<0.01) and forced vital capacity (P<0.01). Right hemi-diaphragm thickness at end of maximum inspiration correlated positively with expiratory volume in 1 second (P<0.01) and forced vital capacity (P<0.01). Left hemi-diaphragm thickness at end of maximum inspiration correlated positively with expiratory volume in 1 second (P<0.01) and forced vital capacity (P<0.01). CONCLUSIONS Diaphragm thickness and motion of the cervical spinal cord injury patients were different from controls. Pulmonary function was impaired in spinal cord injury patients. Ultrasonography of the diaphragm as a non-invasive method that is correlated with pulmonary function.

Induced Pluripotent Stem Cell Transplantation Improves Locomotor Recovery in Rat Models of Spinal Cord Injury: a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIMS: Spinal cord injury (SCI) has long been a subject of great interest in a wide range of scientific fields. Several attempts have been made to demonstrate motor function improvement in rats with SCI after transplantation of induced pluripotent stem cells (iPSC). This systematic review and meta-analysis was designed to summarize the effects of iPSC on locomotor recovery in rat models of SCI. METHODS: We searched the publications in the PubMed, Medline, Science Citation Index, Cochrane Library, CNKI, and Wan-fang databases and the China Biology Medicine disc. Results were analyzed by Review Manager 5.3.0. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Six randomized controlled preclinical trials covering eight comparisons and including 212 rats were selected. The subgroup analyses were based on the following items: different SCI models, cell counts, iPSC sources, iPSC differentiations and transplantation methods. The pooled results indicated that iPSC transplantation significantly improved locomotor recovery of rats after SCI by sustaining beneficial effects, especially in the subgroups of contusion, moderate cell counts (5×105), source of human fetal lung fibroblasts, iPSC-neural precursors and intraspinal injection. CONCLUSION: Our meta-analysis of the effects of iPSC transplantation on locomotor function in SCI models is, to our knowledge, the first meta-analysis in this field. We conclude that iPSC transplantation improves locomotor recovery in rats with SCI, implicating this strategy as an effective therapy. However, more studies are required to validate our conclusions.

Dynamic diffusion tensor imaging of spinal cord contusion: A canine model.

This study aimed to explore the dynamic diffusion tensor imaging (DTI) of changes in spinal cord contusion using a canine model of injury involving rostral and caudal levels. In this study, a spinal cord contusion model was established in female dogs using a custom-made weight-drop lesion device. DTI was performed on dogs with injured spinal cords (n=7) using a Siemens 3.0T MRI scanner at pre-contusion and at 3 h, 24 h, 6 weeks and 12 weeks post-injury. The tissue sections were stained for immunohistochemical analysis. Canine models of spinal cord contusion were created successfully using the weight-drop lesion device. The fractional anisotropy (FA) value of lesion epicenter decreased, while the apparent diffusion coefficient (ADC), mean diffusivity (MD), and radial diffusivity (RD) values increased, and the extent of the curve was apparent gradually. The site and time affected the DTI parameters significantly in the whole spinal cord, ADC (site, P < 0.001 and time, P = 0.077, respectively); FA (site, P < 0.001 and time, P = 0.002, respectively). Immunohistological analysis of GFAP and NF revealed the pathologic changes of reactive astrocytes and axons, as well as the cavity and glial scars occurring during chronic SCI. DTI is a sensitive and noninvasive imaging tool useful to assess edema, hemorrhage, cavity formation, structural damage and reconstruction of axon, and myelin in dogs. The DTI parameters after contusion vary. However, the curves of ADC, MD, and RD were nearly similar and the FA curve was distinct. All the DTI parameters were affected by distance and time.

Gut microbiota dysbiosis in male patients with chronic traumatic complete spinal cord injury.

BACKGROUND: Neurogenic bowel dysfunction (NBD) is a major physical and psychological problem in patients with spinal cord injury (SCI), and gut dysbiosis is commonly occurs in SCI. Here, we document neurogenic bowel management of male patients with chronic traumatic complete SCI in our centre and perform comparative analysis of the gut microbiota between our patients and healthy males. METHODS: A total of 43 male patients with chronic traumatic complete SCI (20 with quadriplegia and 23 with paraplegia) and 23 healthy male adults were enrolled. Clinical data and fresh stool specimens were collected from all participants. Face-to-face interviews were conducted to survey the neurogenic bowel management of 43 patients with SCI. Gut microbiomes were analysed by sequencing of the V3-V4 region of the 16S rRNA gene. RESULTS: NBD was common in adult male patients with chronic traumatic complete SCI. Patients with quadriplegia exhibited a longer time to defecate than did those with paraplegia and had higher NBD scores and heavier neurogenic bowel symptoms. The diversity of the gut microbiota in the SCI group was reduced, and the structural composition was different from that of the healthy adult male group. The abundance of Veillonellaceae and Prevotellaceae increased, while Bacteroidaceae and Bacteroides decreased in the SCI group. The abundance of Bacteroidaceae and Bacteroides in the quadriplegia group and Acidaminococcaceae, Blautia, Porphyromonadaceae, and Lachnoclostridium in the paraplegia group were significantly higher than those in the healthy male group. Serum biomarkers (GLU, HDL, CR, and CRP), NBD defecation time and COURSE had significant correlations with microbial community structure. Microbial community structure was significantly associated with serum biomarkers (GLU, HDL, CR, and CRP), NBD defecation time, and COURSE. CONCLUSIONS: This study presents a comprehensive landscape of the gut microbiota in adult male patients with chronic traumatic complete SCI and documents their neurogenic bowel management. Gut microbiota dysbiosis in SCI patients was correlated with serum biomarkers and NBD symptoms.

Laser immunotherapy for cutaneous squamous cell carcinoma with optimal thermal effects to enhance tumour immunogenicity.

BACKGROUND: Laser immunotherapy is a new anti-cancer therapy combining photothermal therapy and immunostimulation. It can eliminate the tumours by damaging tumour cells directly and promoting the release of damage-associated molecular patterns (DAMPs) to enhance tumour immunogenicity. The aim of this study was to investigate the thermal effects of laser immunotherapy and to evaluate the effectiveness and safety of laser immunotherapy for cutaneous squamous cell carcinoma (cSCC). METHODS: The cell viability and the DAMPs productions of heat-treated cSCC A431 cells in different temperatures were investigated. Laser immunotherapy with the optimal thermal effect for DAMPs production was performed on SKH-1 mice bearing ultraviolet-induced cSCC and a patient suffering from a large refractory cSCC. RESULTS: The temperature in the range of 45-50 °C killing half of A431 cells had an optimal thermal effect for the productions of DAMPs. The thermal effect could be further enhanced by local application of imiquimod, an immunoadjuvant. Laser immunotherapy eliminated most tumours and improved the survival rate of the ultraviolet-induced cSCC-bearing SKH-1 mice (p < 0.05). The patient with cSCC treated by laser immunotherapy experienced a significant tumour reduction after laser immunotherapy increased the amounts of infiltrating lymphocytes in the tumour. No obviously adverse effect was observed in the mice experiment or in the clinical application. CONCLUSIONS: Our results strongly indicate that laser immunotherapy with optimal thermal effects is an effective and safe treatment modality for cSCC.

Exploring the best predictors of fluid responsiveness in patients with septic shock.

OBJECTIVE: To evaluate respiratory variations in carotid and brachial peak velocity and other hemodynamic parameters to predict responsiveness to fluid challenge. METHODS: A prospective observational study was performed on mechanically ventilated patients with septic shock. Outcomes included the measurements of central venous pressure, intrathoracic blood volume index, stroke volume variation (SVV), pleth variability index(PVI), and ultrasound assessments of respiratory variations in inferior vena cava diameter (ΔIVC), carotid Doppler peak velocity (ΔCDPV), and brachial artery peak velocity (ΔVpeak brach). RESULTS: All patients received 200 mL normal saline challenge. There were 27 responders and 22 non-responders. Responders had higher SVV, PVI, ΔIVC, ΔCDPV, and ΔVpeak brach measurements. In addition, all these measurements had statistically significant linear correlations with changes in cardiac index (CI).When responders were defined by ΔCI≥10%, receiver operating characteristics (ROC) curve analysis showed that fluid responsiveness could be predicted:11.5% optimal cut-off 1evels of SVV with sensitivity of 75% and specificity of 85%, 15.5% optimal cut-off 1evels of PVI with sensitivity of 65% and specificity of 80%, 20.5% optimal cut-off 1evels of ΔIVC with sensitivity of 67% and specificity of 77%, 13% optimal cut-off 1evels of ΔCDPV with sensitivity of 78%% and specificity of 90%, 11.7% optimal cut-off 1evels of ΔVpeak brach with sensitivity of 70% and specificity of 80%. CONCLUSION: Ultrasound assessment of ΔIVC and ΔVpeak brach, especially ΔCDPV, could predict fluid responsiveness and might be recommended as a continuous and noninvasive method to monitor functional hemodynamic parameter in mechanically ventilated patients with septic shock.

The immediate effects of therapeutic keyboard music playing for finger training in adults undergoing hand rehabilitation.

[Purpose] The purpose of this study was to examine the immediate effects of therapeutic keyboard music playing on the finger function of subjects' hands through measurements of the joint position error test, surface electromyography, probe reaction time, and writing time. [Subjects and Methods] Ten subjects were divided randomly into experimental and control groups. The experimental group used therapeutic keyboard music playing and the control group used grip training. All subjects were assessed and evaluated by the joint position error test, surface electromyography, probe reaction time, and writing time. [Results] After accomplishing therapeutic keyboard music playing and grip training, surface electromyography of the two groups showed no significant change, but joint position error test, probe reaction time, and writing time obviously improved. [Conclusion] These results suggest that therapeutic keyboard music playing is an effective and novel treatment for improving joint position error test scores, probe reaction time, and writing time, and it should be promoted widely in clinics.

Improved sepsis bundles in the treatment of septic shock: a prospective clinical study.

BACKGROUND: Sepsis bundles can decrease mortality in patients with severe sepsis or septic shock. However, current methods of measuring pressure, such as central venous pressure, are inadequate. This study investigated the effect of improved sepsis bundles informed by pulse-indicated continuous cardiac output. METHODS: We compared the outcome of treatment with sepsis bundles informed by either conventional pressure measurements or pulse-indicated continuous cardiac output. Patients in 2 groups received fluid resuscitation, standard antibiotics, and oxygen therapy. RESULTS: A total of 105 patients with septic shock were randomly divided into 2 groups: the conventional sepsis bundle group (n = 52) or the improved sepsis bundle group (ISBG, n =53). The ISBG significantly reduced the mean Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Significantly fewer ISBG-treated patients received vasoactive drugs compared to conventional sepsis bundle group-treated patients. In addition, patients in the ISBG exhibited a significantly increased arterial blood lactate clearance rate and required less total fluid resuscitation and a shorter duration of mechanical ventilation and stay in the intensive care unit. CONCLUSIONS: Pulse-indicated continuous cardiac output-directed sepsis bundles can reduce the severity of septic shock, provide more accurate fluid resuscitation, and reduce the duration of mechanical ventilation and stay in the intensive care unit.

The Evaluation of Chronic Low Back Pain by Determining the Ratio of the Lumbar Multifidus Muscle Cross-sectional Areas of the Unaffected and Affected Sides.

[Purpose] The primary purpose of this study was to evaluate chronic low back pain by determining the ratio of the cross-sectional areas of the lumbar multifidus of the unaffected and affected sides at the L5 level using the ultrasound imaging. [Subjects and Methods] The subjects were 24 young people (10 males, 14 females) with chronic low back pain lasting for more than 6 months on one side. The visual analog scale (VAS) value of pain was assessed and the cross-sectional areas of the bilateral multifidus muscle were measured with the subjects in a supine position in a resting state using ultrasound imaging. Correlation and linear regression analysis were performed on the VAS and the ratio of the cross-sectional areas of the lumbar multifidus of the unaffected and affected sides. [Results] The VAS and the ratio of the cross-sectional areas of the lumbar multifidus were linearly correlated. [Conclusion] The results of this research indicate that when the ratio of the cross-sectional areas of the lumbar multifidus of the unaffected and affected sides increases, the symptom of chronic low back pain deteriorates.

Comparison of the Efficacy of Different Long-term Interventions on Chronic Low Back Pain Using the Cross-sectional Area of the Multifidus Muscle and the Thickness of the Transversus Abdominis Muscle as Evaluation Indicators.

[Purpose] The purpose of this study was to examine the different effects of long-term intervention between proprioceptive neuromuscular facilitation (PNF) and neuromuscular joint facilitation (NJF) patterns for the pelvis on chronic low back pain as assessed by the cross-sectional area of the multifidus muscle and the thickness of the transversus abdominis muscle. [Subjects] The subjects were 12 young people (five males, seven females) who had experienced chronic low back pain on one side for more than 6 months. [Methods] The subjects were treated by resting, PNF or NJF therapy, and each treatment was administered for one month. Ultrasonography was used to measure the changes in the transversus abdominis muscle thickness and the multifidus muscle cross-sectional area. [Results] The thickness of the transversus abdominis muscle and the cross-sectional area of the multifidus muscle in the NJF group, after resting, increased significantly and were higher than those in the PNF group. [Conclusion] The results show that significantly better improvement can be obtained for chronic low back pain by applying long-term intervention of NJF patterns.

Coordination Between Respiration and Swallowing in Patients With Dysphagia After Cervical Spinal Cord Injury: An Observational Case-Control Study.

PURPOSE: The purpose of the present study was to characterize the differences between respiration and swallowing in patients with dysphagia after cervical spinal cord injury (CSCI) and to explore the underlying physiological changes. METHOD: A total of 95 participants were recruited for bedside swallowing evaluation followed by a flexible endoscopic evaluation of swallowing and surface electromyography with a thermocouple nasal airflow sensor examination: 32 with dysphagia, 33 without dysphagia, and 30 healthy controls. The differences in respiratory patterns, swallowing apnea duration (SAD), inspiratory-expiratory ratio, and swallowing efficiency were observed among healthy adults, CSCI patients with and without dysphagia after CSCI. RESULTS: Compared with those of healthy controls and patients without dysphagia after CSCI, the postswallow respiratory pattern of patients with dysphagia after CSCI was an inspiratory pattern, and the SAD was significantly shorter in patients with dysphagia after CSCI (p < .001). Additionally, the expiratory time in patients with dysphagia was significantly shorter than the inspiratory time, and the swallowing efficiency was reduced, requiring multiple swallows. Moreover, the index of SAD was statistically significant for predicting the development of dysphagia in patients with CSCI (p < .001). CONCLUSION: Patients with CSCI have an inspiratory pattern after swallowing, and the SAD is significantly reduced; SAD can be used as the predictor of dysphagia in patients after CSCI; the pattern of coordination between respiration and swallowing in patients with dysphagia after CSCI is different from that of healthy controls and patients without dysphagia after CSCI. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26524717.

Impact of Frailty on Inpatient Outcomes of Acute Traumatic Spinal Cord Injury: Evidence From US National Inpatient Sample.

OBJECTIVES: Spinal cord injury (SCI) is any spinal cord injury or affliction that results in temporary or permanent impairment of motor or sensory function. This study determined the prevalence of frailty and its impact on in-hospital outcomes of patients admitted with acute traumatic SCI (TSCI). METHODS: This retrospective study extracted data of adults 18 to 85 years with acute TSCI from the US Nationwide Inpatient Sample (NIS) 2016 to 2018. Frailty status were assessed by the 11-factor modified Frailty Index (mFI-11) through claim codes. Patients with an mFI ≥3 were classified as frail. Associations between study variables and in-hospital mortality, discharge status, prolonged length of stay, severe infection, and hospital costs were determined by univariate and multivariable regression analyses. RESULTS: A total of 52,263 TSCI patients were identified, where 12,203 (23.3%) patients were frail. After adjusting for relevant confounders, frailty was independently associated with increased risk for in-hospital mortality [adjusted odds ratio (aOR) = 1.25, 95% CI:1.04-1.49], unfavorable discharge (aOR =1.15, 95% CI: 1.09-1.22), prolonged length of stay (aOR =1.32, 95% CI: 1.24-1.40), and severe infection (aOR =2.52, 95% CI: 2.24-2.83), but not hospital cost. Stratified analyses revealed frailty was associated with higher unfavorable discharge and severe infection regardless of age, Charlson Comorbidity Index, and injury level. CONCLUSIONS: In acute TSCI, frailty is independently associated with increased risk for adverse inpatient outcomes in terms of in-hospital mortality, prolonged hospital stays, unfavorable discharge, and particularly severe infection.

Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury in rats.

AIM: We aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism. METHODS: Rats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post-injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post-injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord. RESULTS: CLP290 and bumetanide alleviated SCI-associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate-Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K+-Cl-cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na+-K+-Cl-cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non-significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group. CONCLUSION: Combined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhances GABAA receptor-mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short-term effect.

Inhibition of phospholipase D promotes neurological function recovery and reduces neuroinflammation after spinal cord injury in mice.

Introduction: Spinal cord injury (SCI) is a severely disabling disease. Hyperactivation of neuroinflammation is one of the main pathophysiological features of secondary SCI, with phospholipid metabolism playing an important role in regulating inflammation. Phospholipase D (PLD), a critical lipid-signaling molecule, is known to be involved in various physiological processes, including the regulation of inflammation. Despite this knowledge, the specific role of PLD in SCI remains unclear. Methods: In this study, we constructed mouse models of SCI and administered PLD inhibitor (FIPI) treatment to investigate the efficacy of PLD. Additionally, transcriptome sequencing and protein microarray analysis of spinal cord tissues were conducted to further elucidate its mechanism of action. Results: The results showed that PLD expression increased after SCI, and inhibition of PLD significantly improved the locomotor ability, reduced glial scarring, and decreased the damage of spinal cord tissues in mice with SCI. Transcriptome sequencing analysis showed that inhibition of PLD altered gene expression in inflammation regulation. Subsequently, the protein microarray analysis of spinal cord tissues revealed variations in numerous inflammatory factors. Biosignature analysis pointed to an association with immunity, thus confirming the results obtained from transcriptome sequencing. Discussion: Collectively, these observations furnish compelling evidence supporting the anti-inflammatory effect of FIPI in the context of SCI, while also offering important insights into the PLD function which may be a potential therapeutic target for SCI.