Quality of life and psychological outcomes of body-weight supported locomotor training in spinal cord injured persons with long-standing incomplete lesions.

STUDY DESIGN: Health-related quality of life (HRQOL) data from two parallel independent single-blinded controlled randomized studies of manual (Study 1) and robotic (Study 2) locomotor training were combined (ClinicalTrials.gov #NCT00854555). OBJECTIVE: To assess effects of body-weight supported locomotor training (BWSLT) programs on HRQOL in persons with long-standing motor incomplete spinal cord injury and poor walking function. SETTINGS: Two inpatient rehabilitation facilities and one outpatient clinic in Norway. METHODS: Data were merged into intervention (locomotor training 60 days) or control group ("usual care"). Participants completed questionnaires before randomization and 2-4 weeks after the study period, including demographic characteristics, HRQOL (36-Item Short-Form Health Status Survey, SF-36), physical activity (The International Physical Activity Questionnaire Short Form, IPAQ-SF), exercise barrier self-efficacy (EBSE), and motivation for training (Behavioral Regulation in Exercise Questionnaire, BREQ). Physical outcomes i.e., Lower extremity motor score (LEMS) was assessed. The main outcome was change in HRQOL. Secondary outcomes included changes in IPAQ-SF, EBSE, BREQ, and physical outcomes. RESULTS: We recruited 37 of 60 predetermined participants. They were autonomously motivated with high baseline physical activity. BWSLT with manual or robot assistance did not improve HRQOL, though LEMS increased in the BWSLT group compared with control group. CONCLUSIONS: The study was underpowered due to recruitment problems. The training programs seem to benefit LEMS, but not other physical outcomes, and had minimal effects on HRQOL, EBSE, and motivation. Autonomous motivation and high physical activity prior to the study possibly limited the attainable outcome benefits, in addition to limitations due to poor baseline physical function.

Robot-assisted locomotor training did not improve walking function in patients with chronic incomplete spinal cord injury: A randomized clinical trial.

OBJECTIVE: To assess the effects of robot-assisted locomotor training in patients with chronic incomplete spinal cord injury. DESIGN: Randomized single-blind controlled clinical trial. SETTING: The intervention site was an outpatient clinic, and pre- and post-evaluations were performed in a rehabilitation hospital. PATIENTS: A total of 24 subjects with American Spinal Injury Association Impairment Scale grades C or D, >?2 years post-injury. INTERVENTIONS: Subjects were randomized to 60 days of robot-assisted locomotor training, or to usual care. METHODS: Walking function, lower extremity muscle strength and balance were assessed single-blinded pre- and post-intervention. RESULTS: After a 9-year recruitment period, only 24 of the planned 30 subjects had been enrolled (mean time since injury 17 (standard deviation (SD) 20) years for all subjects). Walking function, lower extremity muscle strength and balance improved modestly in both groups, with no statistically significant group difference in walking function or muscle strength, whereas postural control declined significantly in the intervention group, compared with controls (p?=?0.03). CONCLUSION: Late-onset robot-assisted locomotor training did not re-establish independent walking function. A modest, but non-significant, effect was seen on muscle strength and balance. However, significant between-group differences were found only in postural control in the control group.

Manually assisted body-weight supported locomotor training does not re-establish walking in non-walking subjects with chronic incomplete spinal cord injury: A randomized clinical trial.

OBJECTIVE: To assess the effects of manually assisted body-weight supported locomotor training in subjects with chronic incomplete spinal cord injury. DESIGN: Randomized controlled clinical trial. SUBJECTS: Twenty subjects with American Spinal Injury Association Impairment Scale grades C or D and > 2 years post-injury. METHODS: Random allocation to 60 days of body-weight supported locomotor training, or usual care, which might include over-ground walking. Walking function, lower extremity muscle strength and balance were blindly evaluated pre-/post-intervention. RESULTS: A small, non-significant improvement in walking function was observed (0.1 m/s (95% confidence interval (95% CI) -0.2, 0.4)), but subjects without baseline gait function, did not re-establish walking. The effect on lower extremity muscle strength was 2.7 points (95% CI -1.4, 6.8). No difference was observed in balance measures. CONCLUSION: Subjects with chronic incomplete spinal cord injury without baseline walking function were unable to re-establish gait with manually assisted body-weight supported locomotor training. A modest, non-significant, improvement was found in strength and walking speed. However, due to study recruitment problems, an effect size that was smaller than anticipated, and large functional heterogeneity among study subjects, the effect of late-onset body-weight supported locomotor training is not clear. Future studies should include larger numbers of subjects with less functional loss and greater functional homogeneity. Intensive training should probably start earlier post-injury.

MicroRNA-208b progressively declines after spinal cord injury in humans and is inversely related to myostatin expression.

The effects of long-term physical inactivity on the expression of microRNAs involved in the regulation of skeletal muscle mass in humans are largely unknown. MicroRNAs are short, noncoding RNAs that fine-tune target expression through mRNA degradation or by inhibiting protein translation. Intronic to the slow, type I, muscle fiber type genes MYH7 and MYH7b, microRNA-208b and microRNA-499-5p are thought to fine-tune the expression of genes important for muscle growth, such as myostatin. Spinal cord injured humans are characterized by both skeletal muscle atrophy and transformation toward fast-twitch, type II fibers. We determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in human skeletal muscle after complete cervical spinal cord injury. We also determined whether these microRNAs altered myostatin expression in rodent skeletal muscle. A progressive decline in skeletal muscle microRNA-208b and microRNA-499-5p expression occurred in humans during the first year after spinal cord injury and with long-standing spinal cord injury. Expression of myostatin was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle after spinal cord injury. Overexpression of microRNA-208b in intact mouse skeletal muscle decreased myostatin expression, whereas microRNA-499-5p was without effect. In conclusion, we provide evidence for an inverse relationship between expression of microRNA-208b and its previously validated target myostatin in humans with severe skeletal muscle atrophy. Moreover, we provide direct evidence that microRNA-208b overexpression decreases myostatin gene expression in intact rodent muscle. Our results implicate that microRNA-208b modulates myostatin expression and this may play a role in the regulation of skeletal muscle mass following spinal cord injury.

Altered content of AMP-activated protein kinase isoforms in skeletal muscle from spinal cord injured subjects.

AMP-activated protein kinase (AMPK) is a pivotal regulator of energy homeostasis. Although downstream targets of AMPK are widely characterized, the physiological factors governing isoform expression of this protein kinase are largely unknown. Nerve/contractile activity has a major impact on the metabolic phenotype of skeletal muscle, therefore likely to influence AMPK isoform expression. Spinal cord injury represents an extreme form of physical inactivity, with concomitant changes in skeletal muscle metabolism. We assessed the influence of longstanding and recent spinal cord injury on protein abundance of AMPK isoforms in human skeletal muscle. We also determined muscle fiber type as a marker of glycolytic or oxidative metabolism. In subjects with longstanding complete injury, protein abundance of the AMPKγ3 subunit, as well as myosin heavy chain (MHC) IIa and IIx, were increased, whereas abundance of the AMPKγ1 subunit and MHC I were decreased. Similarly, abundance of AMPKγ3 and MHC IIa proteins were increased, whereas AMPKα2, -ß1, and -γ1 subunits and MHC I abundance was decreased during the first year following injury, reflecting a more glycolytic phenotype of the skeletal muscle. However, in incomplete cervical lesions, partial recovery of muscle function attenuated the changes in the isoform profile of AMPK and MHC. Furthermore, exercise training (electrically stimulated leg cycling) partly normalized mRNA expression of AMPK isoforms. Thus, physical activity affects the relative expression of AMPK isoforms. In conclusion, skeletal muscle abundance of AMPK isoforms is related to physical activity and/or muscle fiber type. Thus, physical/neuromuscular activity is an important determinant of isoform abundance of AMPK and MCH. This further underscores the need for physical activity as part of a treatment regimen after spinal cord injury to maintain skeletal muscle metabolism.

Reduced antioxidant defense and increased oxidative stress in spinal cord injured patients.

OBJECTIVE: To determine the plasma and urine levels of antioxidants and oxidative stress biomarkers in subjects with spinal cord injury (SCI) the first year after injury. DESIGN: Descriptive 1-year follow-up study. SETTING: Rehabilitation and research center. PARTICIPANTS: SCI subjects (n=37; age range, 18-70 y) consecutively enrolled within the first month after injury. A healthy, able-bodied control group (n=346) was also included. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Blood and urine levels of antioxidants and oxidative stress biomarkers were measured at inclusion and after 3 and 12 months postinjury. RESULTS: One month after injury, the plasma antioxidants (total and oxidized glutathione and 6 different carotenoids and α-tocopherol) were reduced by 19% to 71% among the SCI subjects compared with the controls. The redox potential was reduced by 7% among the SCI subjects. The oxidative stress biomarker urinary 8-epi prostagladin F2α (PGF2α) increased to 161% in the SCI subjects compared with the controls. After 3 and 12 months, most of the antioxidant biomarkers were still significantly reduced compared with the controls, while urinary 8-epi PGF2α had increased to 208% compared with the controls. CONCLUSIONS: The levels of antioxidants were significantly lower, while the marker of oxidative stress was higher in the SCI subjects compared with the controls. This observation demonstrates that SCI patients experience increased oxidative stress and reduced antioxidant defense the first year after injury. Our findings warrant intervention studies where SCI patients receive dietary antioxidant support as part of their rehabilitation.

Influence of chronic and acute spinal cord injury on skeletal muscle Na+-K+-ATPase and phospholemman expression in humans.

Na(+)-K(+)-ATPase is an integral membrane protein crucial for the maintenance of ion homeostasis and skeletal muscle contractibility. Skeletal muscle Na(+)-K(+)-ATPase content displays remarkable plasticity in response to long-term increase in physiological demand, such as exercise training. However, the adaptations in Na(+)-K(+)-ATPase function in response to a suddenly decreased and/or habitually low level of physical activity, especially after a spinal cord injury (SCI), are incompletely known. We tested the hypothesis that skeletal muscle content of Na(+)-K(+)-ATPase and the associated regulatory proteins from the FXYD family is altered in SCI patients in a manner dependent on the severity of the spinal cord lesion and postinjury level of physical activity. Three different groups were studied: 1) six subjects with chronic complete cervical SCI, 2) seven subjects with acute, complete cervical SCI, and 3) six subjects with acute, incomplete cervical SCI. The individuals in groups 2 and 3 were studied at months 1, 3, and 12 postinjury, whereas individuals with chronic SCI were compared with an able-bodied control group. Chronic complete SCI was associated with a marked decrease in [(3)H]ouabain binding site concentration in skeletal muscle as well as reduced protein content of the α(1)-, α(2)-, and ß(1)-subunit of the Na(+)-K(+)-ATPase. In line with this finding, expression of the Na(+)-K(+)-ATPase α(1)- and α(2)-subunits progressively decreased during the first year after complete but not after incomplete SCI. The expression of the regulatory protein phospholemman (PLM or FXYD1) was attenuated after complete, but not incomplete, cervical SCI. In contrast, FXYD5 was substantially upregulated in patients with complete SCI. In conclusion, the severity of the spinal cord lesion and the level of postinjury physical activity in patients with SCI are important factors controlling the expression of Na(+)-K(+)-ATPase and its regulatory proteins PLM and FXYD5.

Differential expression of metabolic genes essential for glucose and lipid metabolism in skeletal muscle from spinal cord injured subjects.

Skeletal muscle plays an important role in the regulation of energy homeostasis; therefore, the ability of skeletal muscle to adapt and alter metabolic gene expression in response to changes in physiological demands is critical for energy balance. Individuals with cervical spinal cord lesions are characterized by tetraplegia, impaired thermoregulation, and altered skeletal muscle morphology. We characterized skeletal muscle metabolic gene expression patterns, as well as protein content, in these individuals to assess the impact of spinal cord injury on critical determinants of skeletal muscle metabolism. Our results demonstrate that mRNA levels and protein expression of skeletal muscle genes essential for glucose storage are reduced, whereas expression of glycolytic genes is reciprocally increased in individuals with spinal cord injury. Furthermore, expression of genes essential for lipid oxidation is coordinately reduced in spinal cord injured subjects, consistent with a marked reduction of mitochondrial proteins. Thus spinal cord injury resulted in a profound and tightly coordinated change in skeletal muscle metabolic gene expression program that is associated with the aberrant metabolic features of the tissue.

Melatonin stimulates release of tissue factor pathway inhibitor from the vascular endothelium.

We previously found an association between the circadian variation of free tissue factor pathway inhibitor (TFPI) and melatonin in able-bodied males and in men with complete cervical spinal cord injuries. We therefore examined whether melatonin modifies production and/or secretion of TFPI in endothelial cells. We sampled supernatants from cultures of primary human umbilical vein endothelial cells (HUVECs) and of human coronary artery endothelial cells (HCAECs), that had been exposed to varying doses (0-300 pg/ml) of melatonin for 0.5-24 h. We then measured the protein concentrations of free TFPI, tissue factor and plasminogen activator inhibitor type 1 (PAI-1). We also measured endothelial TFPI, tissue factor and PAI-1 transcripts using quantitative real-time PCR. Melatonin dose dependently increased free TFPI levels about 25-30-fold in supernatants of both HUVEC and HCAEC, and independent of incubation duration. In contrast, TF and PAI-1 remained unaltered upon increasing doses of melatonin. Neither TFPI mRNAs nor tissue factor mRNAs nor PAI-1-mRNAs were changed in cell cultures added melatonin. The ratio of free TFPI in cell supernatants to free TFPI in cell lysates about doubled upon addition of melatonin, indicating that melatonin increased release from intracellular storages of free TFPI or from membrane-bound free TFPI. Our data indicate that melatonin stimulates vascular endothelial cells to secrete TFPI without altering transcription of the TFPI gene. If melatonin increases TFPI release in a similar fashion in vivo as in vitro, this could have potential clinical implications in both prophylaxis and treatment of thromboembolic events.

[Complications of chronic spinal cord injury]. / Komplikasjoner etter kronisk ryggmargsskade.

BACKGROUND: A spinal cord injury changes body composition and metabolism over time. The main purpose of this article is to provide an overview of what is known about these changes and the consequences of those in the chronic phase, long after the acute injury. MATERIAL AND METHODS: The article is based on own research and clinical experience, as well as a non-systematic search in the PubMed database. RESULTS: The following has been documented for people with spinal cord injury: reduced bone and muscle mass, altered composition of muscle fibre, marked increase of body fat, decreased sensitivity to insulin and leptin and an increased activity in inflammatory signalling pathways. Changes are also demonstrated in hemostatic mechanisms and immune system. INTERPRETATION: Changes in metabolism and hormonal regulation in people with spinal cord injury, may increase the risk of osteoporosis, obesity, cardiovascular disease and type 2 diabetes. Changed body composition and inflammatory activity may contribute to the higher incidence of cardiovascular disease and diabetes/metabolic syndrome, although other important risk factors (such as obesity and high blood pressure) may be absent. It has not been documented that changes in haemostatic mechanisms and the immune system are associated with the increased incidence of thromboembolic complications, severe infections or certain types of cancer.

Employment of persons with spinal cord lesions injured more than 20 years ago.

PURPOSE: The primary objective was to study factors influencing post-injury employment and withdrawal from work in persons who sustained traumatic spinal cord injury (SCI) more than 20 years ago. A secondary objective was to study life satisfaction in the same patients. METHOD: A cross-sectional study with retrospective data of 165 SCI-patients admitted to Sunnaas Rehabilitation Hospital 1961-1982. Multiple logistic regression was used to identify predictors for obtaining work post-injury. A Cox proportional hazards regression model was used to study factors influencing early withdrawal from work, i.e. time from injury until discontinuing employment. RESULTS: Sixty-five percent of the participants were employed at some point after the injury. Thirty-five percent still had work at the time of the survey. The odds of obtaining work after injury were higher in persons of younger age at injury, higher in males versus females, higher for persons with paraplegia versus tetraplegia, and for persons classified as Frankel D-E compared to a more severe SCI. Factors associated with shorter time from injury until discontinuing employment were higher age at injury, incidence of injury after 1975 versus before, and a history of pre-injury medical condition(s). Life satisfaction was better for currently employed participants. CONCLUSION: The study indicates a low employment-rate in persons with SCI, even several years after injury. From the results, we suggest more support, especially to persons of older age at injury and/or with a history of pre-injury medical condition(s), to help them to obtain work and sustain employed for more years after injury.

Mortality after spinal cord injury in Norway.

OBJECTIVES: To study mortality, cause of death and risk indicators for death in Norwegian patients with spinal cord injury. DESIGN: A cross-sectional study with retrospective data. SUBJECTS: All patients (n=387) with traumatic spinal cord injury admitted to Sunnaas Rehabilitation Hospital, Norway, during the period 1961-82. METHODS: Medical records were reviewed retrospectively. Causes of death were collected from Statistics Norway and death certificates. Standardized mortality ratios (SMRs) were calculated for the entire sample and for causes of death. To explore risk indicators for death, a Cox regression model was used. RESULTS: During the observation period, 1961-2002, 142 patients died. The main causes of death were pneumonia/influenza (16%), ischaemic heart diseases (13%) and urogenital diseases (13%). SMR was 1.8 for men and 4.9 for women. Cause-specific SMRs were markedly elevated for urogenital diseases, suicide, pneumonia/influenza, urogenital cancer, and diseases of the digestive system. Risk indicators for death were: higher age at injury, tetraplegia, functionally complete spinal cord injury, pre-injury cardiovascular disease, alcohol or substance abuse and psychiatric diagnosis. CONCLUSION: The SMRs show that life expectancy is reduced in chronic spinal cord injury in Norway, more for women than for men. Cause-specific SMRs and risk indicators suggest that the high mortality rates after spinal cord injury to a certain degree are related to preventable aetiologies. To maximize longevity in chronic spinal cord injury, more attention must be paid to co-morbidity.

Differences in circadian variations of tissue factor pathway inhibitor type 1 between able-bodied and spinal cord injured.

INTRODUCTION: Tissue factor pathway inhibitor type 1 (TFPI) is the physiological inhibitor of the tissue factor pathway of coagulation. TFPI is produced by endothelial cells, and most intravascular TFPI is composed of full-length TFPI associated with the endothelium. Circulating TFPI is mainly truncated and lipoprotein-associated, but a small fraction circulates in a free full-length form. Although hormonal state influences the plasma variation of TFPI between individuals, other factors like temporal variation may be important. Hence, in the current study we aimed at exploring the intra-individual variation with focus on the possible circadian variations of TFPI. MATERIALS AND METHODS: TFPI free and total antigen from 8 able-bodied and 6 tetraplegic men were measured at 12 time points during a 24 h period. RESULTS: TFPI free antigen in the able-bodied exhibited circadian variation with the highest levels (approximately 20% above mean) from 12:00 to 18:00 h and the lowest levels (approximately 15% below mean) at 09:00 and 02:00 h. In contrast, TFPI free antigen in the tetraplegic group showed no circadian variation. TFPI total antigen exhibited circadian variation in neither group, but mean TFPI total antigen was lower in the tetraplegic group compared with the able-bodied (80 versus 110 ng/mL, respectively). Notably, even if TFPI total antigen in both groups did not vary according to any specific circadian rhythm, the intra-individual variation was higher than the assay variation. CONCLUSION: TFPI free antigen exhibited circadian variations in able-bodied, but not in tetraplegic subjects and the able-bodied had higher levels of TFPI total antigen than the tetraplegic group.

Tetraplegic subjects have hyperleptinaemia with marked circadian variation.

OBJECTIVE: The disruption between the brain and the spinal cord leads to a decentralized sympathetic nervous system in people with chronic, cervical spinal cord lesions. These tetraplegic subjects are prone to disorders of energy metabolism and osteoporosis, and they experience alterations in their body composition with a relative accumulation of fat. The adipocyte-derived cytokine leptin is a key signal in caloric intake and energy expenditure, and it might modify bone remodelling, possibly regulated by sympathetic neuronal signalling. In able-bodied subjects leptin exhibits circadian variations, possibly mediated via sympathetic neurones. We have examined the plasma concentration of leptin among tetraplegics, to determine whether plasma leptin in these subjects exhibits circadian variations. MEASUREMENTS AND RESULTS: Blood samples were collected during a 24-h study period from tetraplegic subjects (n = 6) and from able-bodied controls (n = 8). Fasting, tetraplegic subjects had mean plasma concentrations of leptin about four times those of able-bodied controls (P < 0.05). In tetraplegia, plasma leptin was negatively correlated with total lean mass (r =-0.88, P < 0.05) but correlated positively with total fat mass (r = 0.89, P < 0.05). A marked circadian variation in plasma leptin concentrations was more evident in tetraplegia than in able-bodied controls. CONCLUSION: Plasma leptin is markedly elevated and it shows more prominent circadian variations in tetraplegia compared with able-bodied subjects. Possibly the regulation of leptin metabolism is impaired among these patients. This might distort thermogenesis and energy expenditure, thus explaining the enhanced risk of the metabolic syndrome and of osteoporosis among tetraplegic subjects.

Preserved granulocyte formation and function, as well as bone marrow innervation, in subjects with complete spinal cord injury.

Patients with a spinal cord injury are at risk of infections and is partly attributed to immobilization. Their lymphocyte-mediated immunity is impaired and the growth of blood progenitor cells is reduced. An adequate immune response depends on granulocytes being mobilized rapidly and activated properly, at the inflammatory site. Possibly this requires a coordinated interaction between the autonomous nervous system and cells within the haematopoietic bone marrow. Granulocyte function in the spinal cord injured has not been evaluated. Although there is evidence that the bone marrow in rodents is innervated, it is uncertain whether human bone marrow is similarly affected. Microscopy and immunolabelling followed by flow cytometry, showed that blood and bone marrow counts of leucocyte subsets were similar in paraplegic, tetraplegic and control subjects (P > 0.05). Neutrophilic migration and oxygen consumption, as well as eosinophil activation, assayed as release of eosinophilic cationic protein or CD69 expression, were not altered after spinal cord injury (P > 0.05). Cryostat sections of human bone marrow biopsies stained positive with glyoxylic acid, indicating the presence of catecholamine-containing nerves in both the patients and the controls. We conclude that terminal differentiation and formation of granulocytes, as well as their functional capacity, do not depend appreciably on supraspinal nervous regulation.

Impaired circadian variations of haemostatic and fibrinolytic parameters in tetraplegia.

Spinal cord injured patients are at increased risk of developing deep vein thrombosis (DVT). Whether these patients have increased blood levels of prothrombotic markers remains to be clarified. In general, the risk of developing DVT is highest in the morning hours. In healthy humans, several haemostatic and fibrinolytic parameters exhibit circadian variations, but it is not known whether this also applies to those with spinal cord injury. The aim of the present study was to examine possible circadian variations in prothrombotic markers in tetraplegic patients. We studied six patients with complete tetraplegia and eight control subjects with repetitive blood sampling over a 24 h period. While the control subjects showed marked circadian variations in factor VIII activity, prothrombin fragments 1+2 and D-dimer levels, the tetraplegic patients did not (P < 0.05). Circadian variation in plasminogen activator inhibitor type-1 was present in both groups, being most marked (P < 0.05) in tetraplegia. We conclude that the circadian variations of several factors of the haemostatic and fibrinolytic systems are impaired in spinal cord injury. This could possibly reflect a deregulated autonomic nervous system, leading to a dysfunctional link between central and peripheral circadian oscillators.