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The investigation of human cerebrospinal fluid exosome in spinal cord injury.

Spinal cord injury (SCI) leads to severe neurological and functional impairments, yet reliable biomarkers for assessing injury severity and predicting recovery remain limited. Cerebrospinal fluid (CSF) is in direct contact with the central nervous system and provides a valuable source for detecting molecular changes after SCI. Although exosomal microRNAs (miRNAs) and proteins are increasingly recognized as mediators of intercellular communication, the role of human CSF exosomes in SCI has not been systematically investigated. To identify exosome-based biomarkers and potential therapeutic targets, we analyzed CSF and serum exosomes from patients with acute SCI using RNA sequencing and proteomic profiling. Weighted gene co-expression network analysis identified 6 gene modules significantly associated with injury severity and neurological recovery at 3 months. Proteomic analysis revealed a 5-protein panel that distinguished complete from incomplete SCI and a 4-protein panel that predicted neurological improvement. Additionally, 15 CSF-specific and 9 serum-specific exosomal miRNAs were identified independent of injury severity. Among 10 tested miRNAs associated with neurological recovery, 7 regulated astrocyte proliferation, and 6 promoted neurite extension and synapse formation. Overall, this study provides a comprehensive characterization of CSF exosomal miRNAs and proteins in human SCI and identifies molecular signatures associated with injury severity and recovery.

Humans

Effect of impounder contact area on experimental spinal cord injury.

The spinal cords of two groups of dogs were subjected to 500 gm-cm impacts using two different configurations of impounders. The impounders varied only in area of contact with the dural surface. All other parameters were kept constant. With one impounder all of the dogs injured were totally paraplegic. The impounder consistently producing total paraplegia straddled the entire width of the dorsal surface of the spinal cord in a manner corresponding to the posterior arch of a vertebra. The injury produced with this impounder is not only consistently reproducible but bears a closer resemblance to clinical injury such as anterior vertebral dislocation than that produced with a smaller impounder.

Animals

Urethral hypotonicity after suprasacral spinal cord injury.

Established suprasacral spinal cord injuries usually are associated with detrusor hyperreflexia and varying degrees of detrusor-sphincter dyssynergia. Occasionally, such injuries result in detrusor areflexia or urethral hypotonicity or both. The results of the urodynamic evaluation of 4 patients with suprasacral spinal cord injuries are described. Detrusor areflexia and urethral hypotonicity were demonstrated in 3 cases and urethral smooth muscular hypotonia but preserved reflex detrusor function in 1. It is shown that destruction of the thoracolumbar sympathetic outflow can cause the complete loss of urethral smooth muscular closing function and that resting urethral closure is totally independent of preganglionic cholinergic influences.

Adult

Physical therapists' knowledge of sexuality of adults with spinal cord injury.

Helping the adult with spinal cord injury to adjust to sexual limitations is an important and neglected part of his rehabilitation. Health professionals of all fields have been perceived to be deficient in their knowledge of the sexuality of the adult with spinal cord injury. A test with 40 statements reflecting myths, misconceptions, and truths about the effect of spinal cord injury on sexual function was administered to 30 physical therapists responsible for rehabilitating these adults. At least 28 of the 40 items were missed by 10 percent or more of the therapists. Experience and participation in educational programs appeared to contribute to the respondents' knowledge, as reflected by the test, but only experience was a statistically significant variable.

Attitude

Detrusor muscle and sphincteric response to anorectal stimulation in spinal cord injury.

Twelve patients with spinal cord injuries were studied to determine whether the anal sphincter could be used as an index of urethral sphincter activity and to determine the bladder and striated sphincter response to anal and rectal stimulation. Electromyogram (emg) needle electrodes were placed in the external urethral sphincter, external anal sphincter and levator ani. The output of a cystometer was simultaneously recorded on the printout so that the relationship of the striated muscle response to distension of the bladder could be observed. The response to inserting a finger into the external anal canal, external anal sphincter stretch and rectal balloon distension was also observed. The external urethral and anal sphincter activity was closely linked during bladder contraction and anorectal stimulation. The levator ani showed divergent activity. Stretch of the external anal sphincter caused an initial period of increased striated muscle activity, then in 10 of 12 patients abrupt and often marked inhibition of both sphincters and levator ani developed with continued stretch. Ongoing bladder contractions were inhibited and a decrease in bladder tone developed in 7 of 12. Stretch of the rectum produced results similar to those with anal stretch except that bladder facilitation was seen in 4 of 12 patients.

Anal Canal

Pes cavus and claw toes deformity in patients with spinal cord injury and multiple sclerosis.

Patients with spinal cord injury or multiple sclerosis were surveyed for the presence of extreme foot deformities and spasticity. Pes cavus and claw toes were found in eight of 80 spastic spinal cord injury and two of 20 multiple sclerosis patients. Pes cavus and claw toes were not found in 29 flaccid spinal cord injury patients. Pes cavus and claw toes were associated with flexor reflexes which could be elicited by pin prick proximal to the knee, suggesting extreme spasticity--and by low excitatory thresholds for the anterior tibialis as indicated electromyographically. Complications of severe spasticity associated with spinal cord injury and multiple sclerosis include pes cavus and claw toes, mediated in part by spasms of the anterior tibialis.

Adult

Current concepts in the immediate management of acute spinal cord injuries.

The management of acute spinal cord injuries has changed considerably during the past 10 years owing to new information about the pathophysiology of cord trauma and new diagnostic and treatment methods. It is now known that the cord suffers not only from the immediate physical effects of trauma, but also from secondary pathologic processes, such as ischemia and edema, which are treatable in the first few hours after injury. New neuroradiologic and neurophysiological techniques, such as the recording of the somatosensory evoked potential, increase the accuracy of diagnosis and prognosis in the acute phase. Current immediate treatment includes the administration of steroids and mannitol, with careful attention to respiratory and cardiovascular homeostasis, to overcome post-traumatic ischemia and edema, and immobilization of the spine with devices such as the halo. New surgical procedures are used in selected cases to improve neurologic recovery, to provide rigid immobilization of the spine or to allow earlier mobilization of the patient. The care of spinal cord injuries in the acute phase is facilitated by multidisciplinary units.

Animals

Effects of transcutaneous nerve stimulation on the vesicourethral function in spinal cord injury patients.

There were 17 spinal cord injury men with drug-resistant pain who were treated with transcutaneous nerve stimulation. Bladder and sphincter dysfunctions were evaluated by gas cystosphincterometry and rectal sphinctero-electromyography with the patient in 2 different positions. With the use of transcutaneous nerve stimulation for pain we noted no demonstrable urodynamic changes in acute and chronic paraplegics and chronic quadriplegics. However, there was an increase in the urethral pressures and in the rectal electromyogram spike potentials in acute and recent (less than 2 years post-injury) quadriplegics with postural detrusor-striated sphincter dyssynergia. Therefore, caution is necessary when transcutaneous nerve stimulation is used in this particular group of patients since it might be detrimental to the genitourinary tract.

Adult

Effects of testosterone-augmented multimodal exercise intervention in spinal cord injury: a randomized controlled trial.

CONTEXT: Spinal cord injury (SCI) leads to profound muscle atrophy, aerobic deconditioning, and metabolic dysfunction. Exercise-based interventions alone produce modest benefits. Whether testosterone can augment physiologic responses to exercise in this population remains untested. OBJECTIVE: To evaluate efficacy and safety of home-based intervention combining functional electrical stimulation-assisted leg cycling (FES-LC), arm ergometry (AE), and testosterone compared with FES-LC, AE plus placebo in adults with SCI. METHODS: This randomized, placebo-controlled, double-blind trial enrolled 84 adults (76 males and 8 females) aged 19-70 years with SCI (neurologic levels C4-T12; AIS grades A-D). Participants were randomized to multimodality intervention (home-based FES-LC, AE and intramuscular testosterone undecanoate) (n = 38) or control intervention (FES-LC, AE plus placebo) (n = 46) for 16 weeks. The primary outcome was change in aerobic capacity (peak VO2) during AE cardiopulmonary exercise testing. Secondary outcomes included lean mass, hemoglobin, cardiometabolic markers, and safety. RESULTS: Mean (SD) age was 44 (13) years and time since injury was 13.9 (13) years). Between-group changes in peak VO2 were not statistically significant. Within-group improvements were larger in multimodality (∼19% increase; 0.10 L/min; 95% CI, 0.02-0.18 L/min) compared to controls (∼6% increase; 0.06 L/min; 95% CI, -0.01-0.13). The multimodality group gained significantly more lean mass (whole-body:1.84 kg, 95% CI: 0.52-3.16, P = .007; lower extremity 0.92 kg, 95% CI: 0.38-1.45, P = .001), and anemia was corrected in a greater proportion of participants. Adverse event rates were similar between groups. CONCLUSION: A home-based multimodality intervention combining FES-LC, AE, and testosterone was safe and associated with greater improvements in lean mass and hemoglobin. Although between-group differences in aerobic capacity were not statistically significant, greater within-group increases were observed in the multimodality group. These findings may inform future studies of testosterone-augmented exercise interventions for individuals living with SCI.

Humans

Effect of vasodilators and myelotomy on recovery after acute spinal cord injury in rats.

The effect of papaverine, nitroprusside, or myelotomy on the recovery of spinal cord function was studied in rats after acute cord-compression injury. Spinal cord recovery was measured by a quantitative method of clinical assessment previously developed in our laboratory. Neither papaverine nor nitroprusside improved recovery of cord function. Dorsal midline myelotomy extending anteriorly as far as the central canal did not produce significant improvement (p greater than 0.05). However, when the myelotomy extended completely through the cord in the anteroposterior plane significant improvement (p less than 0.01) was obtained.

Animals

Pain in patients with spinal cord injury.

For this study of intractable pain after spinal cord injury (SCI), a questionnaire was developed, pilot-tested and mailed to 356 previously hospitalized SCI patients, 200 (56%) of whom returned the completed questionnaire. Of the respondents, 160 (80%) reported abnormal sensation and 96 (48%) called the discomfort painful. Abnormal sensations were first noted within 6 months of injury by 105 patients, from 7 months to 4 years after injury by 39, and longer than 4 years after injury or unknown by 16. Pain locations varied and were unrelated to the level of lesion. In 30% of those reporting abnormal sensation the location of pain remained stationary, whereas in 17% it changed over time. The intensity of pain was described as severe to extreme by 25%; 44% indicated that it interfered with daily activities. Increase of pain over time was noted by 41%. Activity, inactivity, weather change and overexertion were not frequently identified as aggravating circumstances. Rest and medication were cited as alleviating factors. Approximately 38% of those experiencing pain used medications but only 22% obtained consistent relief from their use. Patients with low level lesions were more willing to exchange a hypothetical chance of recovery and/or loss of reacquired physiologic functions for pain relief than were patients with higher lesions.

Activities of Daily Living

Neurogenic gastroduodenal ulceration and bleeding associated with spinal cord injuries.

Twenty-four of 576 consecutive patients with spinal cord injuries developed acute gastroduodenal ulceration and hemorrhage. Twenty-two were males and two were females: 88% were 12 to 25 years old. Seventeen patients sustained injuries to the spinal cord in sports and recreation related activities. Twenty-three patients had lesions of the spinal cord above the sympathetic outflow. Twenty patients developed gastroduodenal perforation or bleeding within 4 weeks following the injury. Ten patients developed perforation of gastric or duodenal ulcer and "shoulder tip" pain was a symptom of perforation in six patients. Six patients of seven who had gastroscopy and upper GI series were found at laparotomy to have ulcers. Gastric (nine) and duodenal (seven) ulcers were evenly distributed. There were no deaths due to gastroduodenal hemorrhage in the present series. A single cause for the pathogenesis of gastroduodenal ulceration and hemorrhage cannot be pinpointed. However, ischemia of gastric mucosa produced in various ways and altered equilibrium between the parasympathetic and sympathetic neural pathways following trauma to the spinal cord seem to be important in initiating the process.

Acute Disease

Spinal cord injury following aortorenal bypass.

Spinal cord ischemia following abdominal aortic aneurysmectomy is believed to be caused by hypotension, aortic clamping, division of lumbar arteries, and emboli. In this report a patient underwent aortorenal bypass complicated by temporary urinary and rectal sphincter paralysis appearing four days postoperatively. Angiographic studies suggest that the cord damage was caused by microemboli traversing iliolumbar collateral arteries.

Aorta, Abdominal

Urinary tract infections occurring in recent spinal cord injury patients on intermittent catheterization.

During a 28-month interval 70 spinal cord injury patients in the initial rehabilitation hospitalization underwent 5,052 days of intermittent catheterization. Intermittent catheterization was done with a sterile technique and a neomycin-polymyxin irrigant. At the time of transfer to our facility 39 patients were using Foley catheter drainage but no difficulty was encountered when these patients were changed to intermittent cateterization. While on intermittent catheterization 52 urinary tract infections occurred, half caused by gram-positive cocci, 24 by gram-negative bacilli and 2 by Candida albicans. These infections occurred in 38 patients (54 per cent) at an over-all rate of 10.3 infections per 1,000 patient-days of intermittent catheterization. Only 2 infections were symptomatic and these occurred in patients on pass who unilaterally discontinued intermittent catheterization. Only 6 infections were not cured by antimicrobial therapy. Urinary tract infection was less common in patients who had incomplete spinal cord injuries. Infections caused by organisms susceptible to the irrigant containing neomycin-polymyxin occurred almost exclusively in patients catheterized 3 or fewer times daily. Infection was rare after 3 months on intermittent catheterization. Intermittent catheterization with our technique poses little infection hazard and can be introduced readily in acute spinal cord injury patients before transfer to specialized facilities.

Adult

Are spinal cord injury patients more prone to contrast reactions?

A previous investigation has indicated that spinal cord injury patients are more prone to develop reactions to intravenous contrast media. An investigation into the incidence of contrast reaction in 100 spinal cord injury patients undergoing intravenous pylography together with the incidence in a control group of 100 non-paraplegic patients, has been made. This has shown that spinal cord injury patients do not have a higher incidence of reaction. The aetiology of contrast reaction is briefly discussed with particular reference to the paraplegic patient.

Contrast Media

Influence of arterial blood pressure upon central hemorrhagic necrosis after severe spinal cord injury.

To determine the influence of systemic arterial blood pressure upon the pathogenesis of spinal cord injury, we eliminated the increase in systemic blood pressure normally observed after trauma to the spinal cord with the ganglionic blocker chlorisondamine. Blockade of the pressure response did not influence the development of hemorrhagic necrosis in the spinal cord. We conclude that the transient pressure response accompanying spinal cord injury is probably not a major factor in the pathogenesis of hemorrhagic necrosis at the site of the spinal cord injury.

Animals