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1.  The musculoskeletal abnormalities of the Similaun Iceman (“ÖTZI”): clues to chronic pain and possible treatments 
Inflammopharmacology  2012;21(1):11-20.
Background and Introduction
In 1991, a deceased human male was found frozen in a glacier pool in the Italian Alps in north west Italy, and is now carefully preserved in the South Tyrol Museum of Archaeology, in Bolzano, Italy. The bodily tissues of the 5,300 year old male (colloquially referred to as the Iceman or Ötzi) were well preserved despite damage related to freezing, and glacial movement. Associated articles of well-preserved clothing, tools, weapons and other devices were also present and have been studied in detail. Clinical examination and imaging investigations have also shown that the Icemen had experienced possible illnesses in his lifetime and had identifiable areas of arthritis and musculoskeletal injury. This report includes some key observations on the musculoskeletal state of Ötzi and reference to the involvement of tattoo markings. Some aspects about the aetiology of his abnormalities and inflammatory arthritis are considered along with possible treatments that he might have employed.
Methods and results
We (WFK and MK) undertook a clinical musculoskeletal examination of the Iceman, details of which with available photographs and radiographic imaging pertaining to the musculoskeletal findings of the Iceman are reported here. The skin of the Iceman has numerous linear carbon tattoos, which are not of a decorative type. These have been presumed to possibly be “medicinal” tattoos administered for therapeutic reasons and may have been used in acupuncture-like treatment of pain. Spinal imaging identified areas of spinal damage and our observations have provided clues as to possible sites of spinal initiated pain and hence sites for administration of the “medicinal” tattoos. We observed body areas of the Iceman, in which imaging demonstrated arthritis and other forms of long-term musculoskeletal damage, but which do not have adjacent or corresponding “medicinal” tattoos. We contend that the back and leg “medicinal” tattoos correspond directly to sites of chronic right knee and right ankle pain, and left thoracolumbar pain. They also correspond to lower lumbar and sciatic referred radicular pain which may have a contributory cause related to the presence of a transitional lumbar 5 vertebra. Using recent published data (Keller et al. in Nature Commun 3:698, 2012. doi:10.1038/ncomms1701) of the genome structure of the Iceman, we suggest some potential causes of the osteoarthritis or inflammatory joint injury may relate to presence of coronary heart disease (CHD) and Lyme disease (Borrelia burgdorferi) infection. We speculate on possible medical applications of natural products for self-medication.
These observations highlight several diagnostic features of musculoskeletal conditions in the Iceman with the possibility that tattoos may have been used for diagnosis or location of his painful states. The origins of his musculoskeletal conditions are unclear but there are indications that Lyme disease and CHD may have been factors. The associations or use of natural products may give insights into their applications at the time of the life of the Iceman.
PMCID: PMC3560943  PMID: 23096483
Similaun Iceman; Arthritis; Tattoos; Lyme disease
2.  Key Steps in Developing a Cognitive Vaccine against Traumatic Flashbacks: Visuospatial Tetris versus Verbal Pub Quiz 
PLoS ONE  2010;5(11):e13706.
Flashbacks (intrusive memories of a traumatic event) are the hallmark feature of Post Traumatic Stress Disorder, however preventative interventions are lacking. Tetris may offer a ‘cognitive vaccine’ [1] against flashback development after trauma exposure. We previously reported that playing the computer game Tetris soon after viewing traumatic material reduced flashbacks compared to no-task [1]. However, two criticisms need to be addressed for clinical translation: (1) Would all games have this effect via distraction/enjoyment, or might some games even be harmful? (2) Would effects be found if administered several hours post-trauma? Accordingly, we tested Tetris versus an alternative computer game – Pub Quiz – which we hypothesized not to be helpful (Experiments 1 and 2), and extended the intervention interval to 4 hours (Experiment 2).
Methodology/Principal Findings
The trauma film paradigm was used as an experimental analog for flashback development in healthy volunteers. In both experiments, participants viewed traumatic film footage of death and injury before completing one of the following: (1) no-task control condition (2) Tetris or (3) Pub Quiz. Flashbacks were monitored for 1 week. Experiment 1: 30 min after the traumatic film, playing Tetris led to a significant reduction in flashbacks compared to no-task control, whereas Pub Quiz led to a significant increase in flashbacks. Experiment 2: 4 hours post-film, playing Tetris led to a significant reduction in flashbacks compared to no-task control, whereas Pub Quiz did not.
First, computer games can have differential effects post-trauma, as predicted by a cognitive science formulation of trauma memory. In both Experiments, playing Tetris post-trauma film reduced flashbacks. Pub Quiz did not have this effect, even increasing flashbacks in Experiment 1. Thus not all computer games are beneficial or merely distracting post-trauma - some may be harmful. Second, the beneficial effects of Tetris are retained at 4 hours post-trauma. Clinically, this delivers a feasible time-window to administer a post-trauma “cognitive vaccine”.
PMCID: PMC2978094  PMID: 21085661
3.  Effects of Swimming on Functional Recovery after Incomplete Spinal Cord Injury in Rats 
Journal of neurotrauma  2006;23(6):908-919.
One of the most promising rehabilitation strategies for spinal cord injury is weight-supported treadmill training. This strategy seeks to re-train the spinal cord below the level of injury to generate a meaningful pattern of movement. However, the number of step cycles that can be accomplished is limited by the poor weight-bearing capability of the neuromuscular system after injury. We have begun to study swimming as a rehabilitation strategy that allows for high numbers of steps and a high step-cycle frequency in a standard rat model of contusive spinal cord injury. The purpose of the present study was to evaluate the effect of swimming as a rehabilitation strategy in rats with contusion injuries at T9. We used a swimming strategy with or without cutaneous feedback based on original work in the chick by Muir and colleagues. Adult female rats (n = 27) received moderately-severe contusion injuries at T9. Walking and swimming performance were evaluated using the Open-Field Locomotor Scale (BBB; Basso et al., 1995) and a novel swimming assessment, the Louisville Swimming Scale (LSS). Rats that underwent swim-training with or without cutaneous feedback showed a significant improvement in hindlimb function during swimming compared to untrained animals. Rats that underwent swim-training without cutaneous feedback showed less improvement than those trained with cutaneous feedback. Rats in the non-swimming group demonstrated little improvement over the course of the study. All three groups showed the expected improvement in over-ground walking and had similar terminal BBB scores. These findings suggest that animals re-acquire the ability to swim only if trained and that cutaneous feedback improves the re-training process. Further, these data suggest that the normal course of recovery of over-ground walking following moderately-severe contusion injuries at T9 is the result of a re-training process.
PMCID: PMC2831776  PMID: 16774475
contusion injury; rehabilitation; re-training; swimming
4.  Continuing Education Case Study Quiz 
Hospital Pharmacy  2013;48(4):332-333.
Goal— The goal of this program is to educate pharmacists about the use of perampanel for the treatment of multiple sclerosis.
Objectives—At the completion of this program, the reader will be able to:Describe the pharmacology and pharmacokinetics of perampanel.Discuss the risks associated with the use of perampanel.Discuss the potential benefit of perampanel for an individual patient.Apply the information on the use of perampanel to a case study.
PMCID: PMC3839446  PMID: 24421483
anticonvulsants; new drugs; perampanel
5.  Continuing Education Case Study Quiz 
Hospital Pharmacy  2013;48(3):241-242.
Goal—The goal of this program is to educate pharmacists about the use of teriflunomide for the treatment of multiple sclerosis (MS).
Objectives—At the completion of this program, the reader will be able to:Describe the pharmacology and pharmacokinetics of teriflunomide.Discuss the risks associated with the use of teriflunomide.Discuss the potential benefit of teriflunomide for an individual patient.Apply the information on the use of teriflunomide to a case study.
PMCID: PMC3839510  PMID: 24421468
multiple sclerosis; new drugs; teriflunomide
6.  The effect of a daily quiz (TOPday) on self-confidence, enthusiasm, and test results for biomechanics 
Many students in Biomedical Sciences have difficulty understanding biomechanics. In a second-year course, biomechanics is taught in the first week and examined at the end of the fourth week. Knowledge is retained longer if the subject material is repeated. However, how does one encourage students to repeat the subject matter? For this study, we developed ‘two opportunities to practice per day (TOPday)’, consisting of multiple-choice questions on biomechanics with immediate feedback, which were sent via e-mail. We investigated the effect of TOPday on self-confidence, enthusiasm, and test results for biomechanics. All second-year students (n = 95) received a TOPday of biomechanics on every regular course day with increasing difficulty during the course. At the end of the course, a non-anonymous questionnaire was conducted. The students were asked how many TOPday questions they completed (0–6 questions [group A]; 7–18 questions [group B]; 19–24 questions [group C]). Other questions included the appreciation for TOPday, and increase (no/yes) in self-confidence and enthusiasm for biomechanics. Seventy-eight students participated in the examination and completed the questionnaire. The appreciation for TOPday in group A (n = 14), B (n = 23) and C (n = 41) was 7.0 (95 % CI 6.5–7.5), 7.4 (95 % CI 7.0–7.8), and 7.9 (95 % CI 7.6–8.1), respectively (p < 0.01 between A and C). Of the students who actively participated (B and C), 91 and 80 % reported an increase in their self-confidence and enthusiasm, respectively, for biomechanics due to TOPday. In addition, they had a higher test result for biomechanics (p < 0.01) compared with those who did not actively participate (A). In conclusion, the teaching method ‘TOPday’ seems an effective way to encourage students to repeat the subject material, with the extra advantage that students are stimulated to keep on practising for the examination. The appreciation was high and there was a positive association between active participation, on the one hand, and self-confidence, enthusiasm, and test results for biomechanics on the other.
PMCID: PMC3889994  PMID: 24288127
Daily quiz; Biomechanics; Confidence; Enthusiasm; Education; Test results
7.  Continuing Education Case Study Quiz 
Hospital Pharmacy  2013;48(1):57-59.
Goal— The goal of this program is to educate pharmacists about the use of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (df) combination tablet for the treatment of HIV infection.
Objectives—At the completion of this program, the reader will be able to:Describe the pharmacology and pharmacokinetics of elvitegravir/cobicistat/emtricitabine/tenofovir df combination.Discuss the risks associated with the use of elvitegravir/cobicistat/emtricitabine/tenofovir df combination.Discuss the potential benefit of elvitegravir/cobicistat/emtricitabine/tenofovir df combination for an individual patient.Apply the information on the use of elvitegravir/cobicistat/emtricitabine/tenofovir df combination to a case study.
PMCID: PMC3905829  PMID: 24550569
cobicistat; elvitegravir; emtricitabine; HIV; new drugs; obesity; phentermine; topiramate; Stribild; tenofovir disoproxil fumarate
8.  Continuing Education Case Study Quiz 
Hospital Pharmacy  2013;48(2):153-155.
The goal of this program is to educate pharmacists about the use of linaclotide for the treatment of irritable bowel syndrome and constipation.
At the completion of this program, the reader will be able to:Describe the pharmacology and pharmacokinetics of linaclotide.Discuss the risks associated with the use of linaclotide.Discuss the potential benefit of linaclotide for an individual patient.Apply the information on the use of linaclotide to a case study.
PMCID: PMC3905830  PMID: 24550570
constipation; linaclotide; new drugs
9.  Spontaneous Development of Full Weight-Supported Stepping after Complete Spinal Cord Transection in the Neonatal Opossum, Monodelphis domestica 
PLoS ONE  2011;6(11):e26826.
Spinal cord trauma in the adult nervous system usually results in permanent loss of function below the injury level. The immature spinal cord has greater capacity for repair and can develop considerable functionality by adulthood. This study used the marsupial laboratory opossum Monodelphis domestica, which is born at a very early stage of neural development. Complete spinal cord transection was made in the lower-thoracic region of pups at postnatal-day 7 (P7) or P28, and the animals grew to adulthood. Injury at P7 resulted in a dense neuronal tissue bridge that connected the two ends of the cord; retrograde neuronal labelling indicated that supraspinal and propriospinal innervation spanned the injury site. This repair was associated with pronounced behavioural recovery, coordinated gait and an ability to use hindlimbs when swimming. Injury at P28 resulted in a cyst-like cavity encased in scar tissue forming at the injury site. Using retrograde labelling, no labelled brainstem or propriospinal neurons were found above the lesion, indicating that detectable neuronal connectivity had not spanned the injury site. However, these animals could use their hindlimbs to take weight-supporting steps but could not use their hindlimbs when swimming. White matter, demonstrated by Luxol Fast Blue staining, was present in the injury site of P7- but not P28-injured animals. Overall, these studies demonstrated that provided spinal injury occurs early in development, regrowth of supraspinal innervation is possible. This repair appears to lead to improved functional outcomes. At older ages, even without detectable axonal growth spanning the injury site, substantial development of locomotion was still possible. This outcome is discussed in conjunction with preliminary findings of differences in the local propriospinal circuits following spinal cord injury (demonstrated with fluororuby labelling), which may underlie the weight bearing locomotion observed in the apparent absence of axons bridging the lesion site in P28-injured Monodelphis.
PMCID: PMC3206848  PMID: 22073202
10.  The Louisville Swim Scale: A Novel Assessment of Hindlimb Function following Spinal Cord Injury in Adult Rats 
Journal of neurotrauma  2006;23(11):1654-1670.
The majority of animal studies examining the recovery of function following spinal cord injury use the BBB Open-Field Locomotor Scale as a primary outcome measure. However, it is now well known that rehabilitation strategies can bring about significant improvements in hindlimb function in some animal models. Thus, improvements in walking following spinal cord injury in rats may be influenced by differences in activity levels and housing conditions during the first few weeks post-injury. Swimming is a natural form of locomotion that animals are not normally exposed to in the laboratory setting. We hypothesized that deficits in, and functional recovery of, swimming would accurately represent the locomotor capability of the nervous system in the absence of any retraining effects. To test this hypothesis, we have compared the recovery of walking and swimming in rats following a range of standardized spinal cord injuries and two different retraining strategies. In order to assess swimming, we developed a rating system we call the Louisville Swimming Scale (LSS) that evaluates three characteristics of swimming that are highly altered by spinal cord injury— namely, hindlimb movement, forelimb dependency, and body position. The data indicate that the LSS is a sensitive and reliable method of determining swimming ability and the improvement in hindlimb function after standardized contusion injury of the thoracic spinal cord. Furthermore, the data suggests that when used in conjunction with the BBB Open-field Locomotor Scale, the LSS assesses locomotor capabilities that are not influenced by a retraining effect.
PMCID: PMC2833969  PMID: 17115911
swimming; functional recovery; contusion injury; outcome measure
11.  Artificial Discs for Lumbar and Cervical Degenerative Disc Disease –Update 
Executive Summary
To assess the safety and efficacy of artificial disc replacement (ADR) technology for degenerative disc disease (DDD).
Clinical Need
Degenerative disc disease is the term used to describe the deterioration of 1 or more intervertebral discs of the spine. The prevalence of DDD is roughly described in proportion to age such that 40% of people aged 40 years have DDD, increasing to 80% among those aged 80 years or older. Low back pain is a common symptom of lumbar DDD; neck and arm pain are common symptoms of cervical DDD. Nonsurgical treatments can be used to relieve pain and minimize disability associated with DDD. However, it is estimated that about 10% to 20% of people with lumbar DDD and up to 30% with cervical DDD will be unresponsive to nonsurgical treatments. In these cases, surgical treatment is considered. Spinal fusion (arthrodesis) is the process of fusing or joining 2 bones and is considered the surgical gold standard for DDD.
Artificial disc replacement is the replacement of the degenerated intervertebral disc with an artificial disc in people with DDD of the lumbar or cervical spine that has been unresponsive to nonsurgical treatments for at least 6 months. Unlike spinal fusion, ADR preserves movement of the spine, which is thought to reduce or prevent the development of adjacent segment degeneration. Additionally, a bone graft is not required for ADR, and this alleviates complications, including bone graft donor site pain and pseudoarthrosis. It is estimated that about 5% of patients who require surgery for DDD will be candidates for ADR.
Review Strategy
The Medical Advisory Secretariat conducted a computerized search of the literature published between 2003 and September 2005 to answer the following questions:
What is the effectiveness of ADR in people with DDD of the lumbar or cervical regions of the spine compared with spinal fusion surgery?
Does an artificial disc reduce the incidence of adjacent segment degeneration (ASD) compared with spinal fusion?
What is the rate of major complications (device failure, reoperation) with artificial discs compared with surgical spinal fusion?
One reviewer evaluated the internal validity of the primary studies using the criteria outlined in the Cochrane Musculoskeletal Injuries Group Quality Assessment Tool. The quality of concealment allocation was rated as: A, clearly yes; B, unclear; or C, clearly no. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A random effects model meta-analysis was conducted when data were available from 2 or more randomized controlled trials (RCTs) and when there was no statistical and or clinical heterogeneity among studies. Bayesian analyses were undertaken to do the following:
Examine the influence of missing data on clinical success rates;
Compute the probability that artificial discs were superior to spinal fusion (on the basis of clinical success rates);
Examine whether the results were sensitive to the choice of noninferiority margin.
Summary of Findings
The literature search yielded 140 citations. Of these, 1 Cochrane systematic review, 1 RCT, and 10 case series were included in this review. Unpublished data from an RCT reported in the grey literature were obtained from the manufacturer of the device. The search also yielded 8 health technology assessments evaluating ADR that are also included in this review.
Six of the 8 health technology assessments concluded that there is insufficient evidence to support the use of either lumbar or cervical ADR. The results of the remaining 2 assessments (one each for lumbar and cervical ADR) led to a National Institute for Clinical Excellence guidance document supporting the safety and effectiveness of lumbar and cervical ADR with the proviso that an ongoing audit of all clinical outcomes be undertaken owing to a lack of long-term outcome data from clinical trials.
Regarding lumbar ADR, data were available from 2 noninferiority RCTs to complete a meta-analysis. The following clinical, health systems, and adverse event outcome measures were synthesized: primary outcome of clinical success, Oswestry Disability Index (ODI) scores, pain VAS scores, patient satisfaction, duration of surgery, amount of blood loss, length of hospital stay, rate of device failure, and rate of reoperation.
The meta-analysis of overall clinical success supported the noninferiority of lumbar ADR compared with spinal fusion at 24-month follow-up. Of the remaining clinical outcome measures (ODI, pain VAS scores, SF-36 scores [mental and physical components], patient satisfaction, and return to work status), only patient satisfaction and scores on the physical component scale of the SF-36 questionnaire were significantly improved in favour of lumbar ADR compared with spinal fusion at 24 months follow-up. Blood loss and surgical time showed statistical heterogeneity; therefore, meta-analysis results are not interpretable. Length of hospital stay was significantly shorter in patients receiving the ADR compared with controls. Neither the number of device failures nor the number of neurological complications at 24 months was statistically significantly different between the ADR and fusion treatment groups. However, there was a trend towards fewer neurological complications at 24 months in the ADR treatment group compared with the spinal fusion treatment group.
Results of the Bayesian analyses indicated that the influence of missing data on the outcome measure of clinical success was minimal. The Bayesian model indicated that the probability for ADR being better than spinal fusion was 79%. The probability of ADR being noninferior to spinal fusion using a -10% noninferiority bound was 92%, and using a -15% noninferiority bound was 94%. The probability of artificial discs being superior to spinal fusion in a future trial was 73%.
Six case series were reviewed, mainly to characterize the rate of major complications for lumbar ADR. The Medical Advisory Secretariat defined a major complication as any reoperation; device failure necessitating a revision, removal or reoperation; or life-threatening event. The rates of major complications ranged from 0% to 13% per device implanted. Only 1 study reported the rate of ASD, which was detected in 2 (2%) of the 100 people 11 years after surgery.
There were no RCT data available for cervical ADR; therefore, data from 4 case series were reviewed for evidence of effectiveness and safety. Because data were sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time.
The rate of major complications was assessed up to 2 years after surgery. It was found to range from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature.
The total cost of a lumbar ADR procedure is $15,371 (Cdn; including costs related to the device, physician, and procedure). The total cost of a lumbar fusion surgery procedure is $11,311 (Cdn; including physicians’ and procedural costs).
Lumbar Artificial Disc Replacement
Since the 2004 Medical Advisory Secretariat health technology policy assessment, data from 2 RCTs and 6 case series assessing the effectiveness and adverse events profile of lumbar ADR to treat DDD has become available. The GRADE quality of this evidence is moderate for effectiveness and for short-term (2-year follow-up) complications; it is very low for ASD.
The effectiveness of lumbar ADR is not inferior to that of spinal fusion for the treatment of lumbar DDD. The rates for device failure and neurological complications 2 years after surgery did not differ between ADR and fusion patients. Based on a Bayesian meta-analysis, lumbar ADR is 79% superior to lumbar spinal fusion.
The rate of major complications after lumbar ADR is between 0% and 13% per device implanted. The rate of ASD in 1 case series was 2% over an 11-year follow-up period.
Outcome data for lumbar ADR beyond a 2-year follow-up are not yet available.
Cervical Artificial Disc Replacement
Since the 2004 Medical Advisory Secretariat health technology policy assessment, 4 case series have been added to the body of evidence assessing the effectiveness and adverse events profile of cervical ADR to treat DDD. The GRADE quality of this evidence is very low for effectiveness as well as for the adverse events profile. Sparse outcome data are available.
Because data are sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time.
The rate of major complications was assessed up to 2 years after surgery; it ranged from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature.
PMCID: PMC3379529  PMID: 23074480
12.  Extensive Neuronal Differentiation of Human Neural Stem Cell Grafts in Adult Rat Spinal Cord 
PLoS Medicine  2007;4(2):e39.
Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages.
Methods and Findings
In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter.
NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections.
When neural stem cells from human fetal spinal cord were grafted into the lumbar cord of normal or injured adult nude rats, substantial neuronal differentiation was found.
Editors' Summary
Every year, spinal cord injuries, many caused by road traffic accidents, paralyze about 11,000 people in the US. This paralysis occurs because the spinal cord is the main communication highway between the body and the brain. Information from the skin and other sensory organs is transmitted to the brain along the spinal cord by bundles of neurons, nervous system cells that transmit and receive messages. The brain then sends information back down the spinal cord to control movement, breathing, and other bodily functions. The bones of the spine normally protect the spinal cord but, if these are broken or dislocated, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord can paralyze the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause many other medical problems, including the loss of bowel and bladder control. Although the deleterious effects of spinal cord injuries can be minimized by quickly immobilizing the patient and using drugs to reduce inflammation, the damaged nerve fibers never regrow. Consequently, spinal cord injury is permanent.
Why Was This Study Done?
Scientists are currently searching for ways to reverse spinal cord damage. One potential approach is to replace the damaged neurons using neural stem cells (NSCs). These cells, which can be isolated from embryos and from some areas of the adult nervous system, are able to develop into all the specialized cells types of the nervous system. However, because most attempts to repair spinal cord damage with NSC transplants have been unsuccessful, many scientists believe that the environment of the spinal cord is unsuitable for nerve regeneration. In this study, the researchers have investigated what happens to NSCs derived from the spinal cord of a human fetus after transplantation into the spinal cord of adult rats.
What Did the Researchers Do and Find?
The researchers injected human NSCs that they had grown in dishes into the spinal cord of intact nude rats (animals that lack a functioning immune system and so do not destroy human cells) and into nude rats whose spinal cord had been damaged at the transplantation site. The survival and fate of the transplanted cells was assessed by staining thin slices of spinal cord with an antibody that binds to a human-specific protein and with antibodies that recognize proteins specific to NSCs, neurons, or other nervous system cells. The researchers report that the human cells survived well in the adult spinal cord of the injured and normal rats and migrated into the gray matter of the spinal cord (which contains neuronal cell bodies) and into the white matter (which contains the long extensions of nerve cells that carry nerve impulses). 75% and 60% of the human cells in the gray and white matter, respectively, contained a neuron-specific protein six months after transplantation but only 10% of those in the membrane surrounding the spinal cord became neurons; the rest developed into astrocytes (another nervous system cell type) or remained as stem cells. Finally, many of the human-derived neurons made the neurotransmitter GABA (one of the chemicals that transfers messages between neurons) and made contacts with host spinal cord neurons.
What Do These Findings Mean?
These findings suggest that human NSC grafts can, after all, develop into neurons (predominantly GABA-producing neurons) in normal and injured adult spinal cord and integrate into the existing spinal cord if the conditions are right. Although these animal experiments suggest that NSC transplants might help people with spinal injuries, they have some important limitations. For example, the spinal cord lesions used here are mild and unlike those seen in human patients. This and the use of nude rats might have reduced the scarring in the damaged spinal cord that is often a major barrier to nerve regeneration. Furthermore, the researchers did not test whether NSC transplants provide functional improvements after spinal cord injury. However, since other researchers have also recently reported that NSCs can grow and develop into neurons in injured adult spinal cord, these new results further strengthen hopes it might eventually be possible to use human NSCs to repair damaged spinal cords.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Institute of Neurological Disorders and Stroke provides information on spinal cord injury and current spinal cord research
Spinal Research (a UK charity) offers information on spinal cord injury and repair
The US National Spinal Cord Injury Association Web site contains factsheets on spinal cord injuries
MedlinePlus encyclopedia has pages on spinal cord trauma and interactive tutorials on spinal cord injury
The International Society for Stem Cell Research offers information on all sorts of stem cells including NSCs
The US National Human Neural Stem Cell Resource provides information on human NSCs, including the current US government's stance on stem cell research
PMCID: PMC1796906  PMID: 17298165
13.  Swimming as a Model of Task-Specific Locomotor Retraining After Spinal Cord Injury in the Rat 
The authors have shown that rats can be retrained to swim after a moderately severe thoracic spinal cord contusion. They also found that improvements in body position and hindlimb activity occurred rapidly over the first 2 weeks of training, reaching a plateau by week 4. Overground walking was not influenced by swim training, suggesting that swimming may be a task-specific model of locomotor retraining.
To provide a quantitative description of hindlimb movements of uninjured adult rats during swimming, and then after injury and retraining.
The authors used a novel and streamlined kinematic assessment of swimming in which each limb is described in 2 dimensions, as 3 segments and 2 angles.
The kinematics of uninjured rats do not change over 4 weeks of daily swimming, suggesting that acclimatization does not involve refinements in hindlimb movement. After spinal cord injury, retraining involved increases in hindlimb excursion and improved limb position, but the velocity of the movements remained slow.
These data suggest that the activity pattern of swimming is hardwired in the rat spinal cord. After spinal cord injury, repetition is sufficient to bring about significant improvements in the pattern of hindlimb movement but does not improve the forces generated, leaving the animals with persistent deficits. These data support the concept that force (load) and pattern generation (recruitment) are independent and may have to be managed together with respect to postinjury rehabilitation.
PMCID: PMC2836886  PMID: 19270266
Spinal cord injury; Swimming; Task-specific learning; Rat; Locomotor retraining; Rehabilitation
14.  Swim Training Initiated Acutely after Spinal Cord Injury Is Ineffective and Induces Extravasation In and Around the Epicenter 
Journal of Neurotrauma  2009;26(7):1017-1027.
Activity-based rehabilitation is a promising strategy for improving functional recovery following spinal cord injury (SCI). While results from both clinical and animal studies have shown that a variety of approaches can be effective, debate still exists regarding the optimal post-injury period to apply rehabilitation. We recently demonstrated that rats with moderately severe thoracic contusive SCI can be re-trained to swim when training is initiated 2 weeks after injury and that swim training had no effect on the recovery of overground locomotion. We concluded that swim training is a task-specific model of post-SCI activity-based rehabilitation. In the present study, we ask if re-training initiated acutely is more or less effective than when initiated at 2 weeks post-injury. Using the Louisville Swim Scale, an 18-point swimming assessment, supplemented by kinematic assessment of hindlimb movement during swimming, we report that acute re-training is less effective than training initiated at 2 weeks. Using the bioluminescent protein luciferase as a blood-borne macromolecular marker, we also show a significant increase in extravasation in and around the site of SCI following only 8 min of swimming at 3 days post-injury. Taken together, these results suggest that acute re-training in a rat model of SCI may compromise rehabilitation efforts via mechanisms that may involve one or more secondary injury cascades, including acute spinal microvascular dysfunction.
PMCID: PMC2848951  PMID: 19331515
activity-based rehabilitation; microvascular; rat; spinal cord injury; swimming
15.  Swim Training Initiated Acutely after Spinal Cord Injury Is Ineffective and Induces Extravasation In and Around the Epicenter 
Journal of neurotrauma  2009;26(7):10.1089/neu.2008-0829.
Activity-based rehabilitation is a promising strategy for improving functional recovery following spinal cord injury (SCI). While results from both clinical and animal studies have shown that a variety of approaches can be effective, debate still exists regarding the optimal post-injury period to apply rehabilitation. We recently demonstrated that rats with moderately severe thoracic contusive SCI can be re-trained to swim when training is initiated 2 weeks after injury and that swim training had no effect on the recovery of overground locomotion. We concluded that swim training is a task-specific model of post-SCI activity-based rehabilitation. In the present study, we ask if re-training initiated acutely is more or less effective than when initiated at 2 weeks post-injury. Using the Louisville Swim Scale, an 18-point swimming assessment, supplemented by kinematic assessment of hindlimb movement during swimming, we report that acute re-training is less effective than training initiated at 2 weeks. Using the bioluminescent protein luciferase as a blood-borne macromolecular marker, we also show a significant increase in extravasation in and around the site of SCI following only 8 min of swimming at 3 days post-injury. Taken together, these results suggest that acute re-training in a rat model of SCI may compromise rehabilitation efforts via mechanisms that may involve one or more secondary injury cascades, including acute spinal microvascular dysfunction.
PMCID: PMC2848951  PMID: 19331515
activity-based rehabilitation; microvascular; rat; spinal cord injury; swimming
16.  The Animal Model of Spinal Cord Injury as an Experimental Pain Model 
Pain, which remains largely unsolved, is one of the most crucial problems for spinal cord injury patients. Due to sensory problems, as well as motor dysfunctions, spinal cord injury research has proven to be complex and difficult. Furthermore, many types of pain are associated with spinal cord injury, such as neuropathic, visceral, and musculoskeletal pain. Many animal models of spinal cord injury exist to emulate clinical situations, which could help to determine common mechanisms of pathology. However, results can be easily misunderstood and falsely interpreted. Therefore, it is important to fully understand the symptoms of human spinal cord injury, as well as the various spinal cord injury models and the possible pathologies. The present paper summarizes results from animal models of spinal cord injury, as well as the most effective use of these models.
PMCID: PMC3062973  PMID: 21436995
17.  Meeting Physical Activity Guidelines and Musculoskeletal Injury: The WIN Study 
The United States Department of Health and Human Services disseminated physical activity guidelines for Americans in 2008. The guidelines are based on appropriate quantities of moderate-to-vigorous aerobic physical activity and resistance exercise associated with decreased morbidity and mortality risk and increased health benefits. However, increases in physical activity levels are associated with increased risk of musculoskeletal injuries. We related the amount and type of physical activity conducted on a weekly basis with the risk of musculoskeletal injury.
Prospective, observational study using weekly Internet tracking of moderate-to-vigorous physical activity and resistance exercise behaviors and musculoskeletal injuries in 909 community-dwelling women for up to 3 years. Primary outcome was self-reported musculoskeletal injuries (total, physical activity-related, and non physical activity-related) interrupting typical daily work and/or exercise behaviors for ≥2 days or necessitating health care provider visit.
Meeting versus not meeting physical activity guidelines was associated with more musculoskeletal injuries during physical activity (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.05 – 1.85, P = 0.02), but was not associated with musculoskeletal injuries unrelated to physical activity (HR = 0.99, 95% CI = 0.75 – 1.29, P = 0.92), or with musculoskeletal injuries overall (HR = 1.15, 95% CI = 0.95 – 1.39, P = 0.14).
Results illustrate the risk of musculoskeletal injury with physical activity. Musculoskeletal injury risk rises with increasing physical activity. Despite this modest increase in musculoskeletal injuries, the known benefits of aerobic and resistance physical activities should not hinder physicians from encouraging patients to meet current physical activity guidelines for both moderate-to-vigorous exercise and resistance exercise behaviors with the intent of achieving health benefits.
PMCID: PMC3445731  PMID: 22525778
18.  Age-Dependent Transcriptome and Proteome Following Transection of Neonatal Spinal Cord of Monodelphis domestica (South American Grey Short-Tailed Opossum) 
PLoS ONE  2014;9(6):e99080.
This study describes a combined transcriptome and proteome analysis of Monodelphis domestica response to spinal cord injury at two different postnatal ages. Previously we showed that complete transection at postnatal day 7 (P7) is followed by profuse axon growth across the lesion with near-normal locomotion and swimming when adult. In contrast, at P28 there is no axon growth across the lesion, the animals exhibit weight-bearing locomotion, but cannot use hind limbs when swimming. Here we examined changes in gene and protein expression in the segment of spinal cord rostral to the lesion at 24 h after transection at P7 and at P28. Following injury at P7 only forty genes changed (all increased expression); most were immune/inflammatory genes. Following injury at P28 many more genes changed their expression and the magnitude of change for some genes was strikingly greater. Again many were associated with the immune/inflammation response. In functional groups known to be inhibitory to regeneration in adult cords the expression changes were generally muted, in some cases opposite to that required to account for neurite inhibition. For example myelin basic protein expression was reduced following injury at P28 both at the gene and protein levels. Only four genes from families with extracellular matrix functions thought to influence neurite outgrowth in adult injured cords showed substantial changes in expression following injury at P28: Olfactomedin 4 (Olfm4, 480 fold compared to controls), matrix metallopeptidase (Mmp1, 104 fold), papilin (Papln, 152 fold) and integrin α4 (Itga4, 57 fold). These data provide a resource for investigation of a priori hypotheses in future studies of mechanisms of spinal cord regeneration in immature animals compared to lack of regeneration at more mature stages.
PMCID: PMC4051688  PMID: 24914927
19.  Diagnoses and factors associated with medical evacuation and return to duty among nonmilitary personnel participating in military operations in Iraq and Afghanistan 
Nonmilitary personnel play an increasingly critical role in modern wars. Stark differences exist between the demographic characteristics, training and missions of military and nonmilitary members. We examined the differences in types of injury and rates of returning to duty among nonmilitary and military personnel participating in military operations in Iraq and Afghanistan.
We collected data for nonmilitary personnel medically evacuated from military operations in Iraq and Afghanistan between 2004 and 2007. We compared injury categories and return-to-duty rates in this group with previously published data for military personnel and identified factors associated with return to duty.
Of the 2155 medically evacuated nonmilitary personnel, 74.7% did not return to duty. War-related injuries in this group accounted for 25.6% of the evacuations, the most common causes being combat-related injuries (55.4%) and musculoskeletal/spinal injuries (22.9%). Among individuals with non–war-related injuries, musculoskeletal injuries accounted for 17.8% of evacuations. Diagnoses associated with the highest return-to-duty rates in the group of nonmilitary personnel were psychiatric diagnoses (15.6%) among those with war-related injuries and noncardiac chest or abdominal pain (44.0%) among those with non–war-related injuries. Compared with military personnel, nonmilitary personnel with war-related injuries were less likely to return to duty (4.4% v. 5.9%, p = 0.001) but more likely to return to duty after non–war-related injuries (32.5% v. 30.7%, p = 0.001).
Compared with military personnel, nonmilitary personnel were more likely to be evacuated with non–war-related injuries but more likely to return to duty after such injuries. For evacuations because of war-related injuries, this trend was reversed.
PMCID: PMC3060214  PMID: 21324873
20.  Temporal Profile of Endogenous Anatomical Repair and Functional Recovery following Spinal Cord Injury in Adult Zebrafish 
PLoS ONE  2014;9(8):e105857.
Regenerated cerebrospinal axons are considered to be involved in the spontaneous recovery of swimming ability following a spinal cord injury in adult zebrafish. We employed behavioral analysis, neuronal tracing, and immunocytochemistry to determine the exact temporal relationship between swimming ability and regenerated cerebrospinal axon number in adult zebrafish with a complete spinal cord transection. Between two and eight weeks post-lesion, swimming gradually improved to 44% of sham-injured zebrafish. Neurons within the reticular formation, magnocellular octaval nucleus, and nucleus of the medial longitudinal fascicle grew their axon across and at least four millimeters beyond the lesion. The largest increases in swimming ability and number of regenerated cerebrospinal axons were observed between two and four weeks post-lesion. Regression analyses revealed a significant correlation between swimming ability and the number of regenerated axons. Our results indicate the involvement of cerebrospinal axons in swimming recovery after spinal cord injury in adult zebrafish.
PMCID: PMC4144916  PMID: 25157957
21.  Cervical spine injuries resulting from diving accidents in swimming pools: outcome of 34 patients 
European Spine Journal  2009;19(4):552-557.
Cervical spine injuries after diving into private swimming pools can lead to dramatic consequences. We reviewed 34 patients hospitalized in our center between 1996 and 2006. Data was collected from their initial admission and from follow-up appointments. The injuries were sustained by young men in 97% (mean age 27) and the majority happened during the summer (88%). Fractures were at C5–C7 in 70%. American Spinal Injury Association class (ASIA) on admission was A for 8 patients, B for 4, C for 4, D for 1, and E for 17. There were 23 surgical spine stabilizations. Final ASIA class was A for 6 patients, B for 1, C for 3, D for 5, and E for 18. The mean duration of hospitalization was 21.3 days in our neurosurgical center (mean overall cost: 36,000 Euros/patient) plus 10.6 months in rehabilitation center for the 15 patients admitted who had an ASIA class A to C. Mean overall direct cost for a patient with class A is almost 300,000 Euros, compared to around 10,000 Euros for patients with class D and E. In addition, a profound impact on personal and professional life was seen in many cases including 11 divorces and 7 job losses. Dangerous diving into swimming pools can result in spinal injuries with drastic consequences, including permanent physical disability and a profound impact on socio-professional status. Moreover, there are significant financial costs to society. Better prevention strategies should be implemented to reduce the impact of this public health problem.
PMCID: PMC2899837  PMID: 19956985
Cervical trauma; Diving accident; Outcome; Spine cord injury
22.  Chiropractic treatment approaches for spinal musculoskeletal conditions: a cross-sectional survey 
There are several chiropractic spinal manipulative technique systems. However, there is limited research differentiating the efficacy of these techniques. Additionally, chiropractors may also use ancillary procedures in the treatment of musculoskeletal pain, a variable that also needs to be considered when measuring the efficacy of chiropractic therapy. No data is currently available regarding the frequency of usage of chiropractic technique systems or ancillary procedures for the treatment of specific musculoskeletal conditions. Knowing which technique systems and ancillary procedures are used most frequently may help to direct future research. The aim of this research was to provide insight into which treatment approaches are used most frequently by Australian chiropractors to treat spinal musculoskeletal conditions.
Cross-sectional survey design. The survey was sent online to the members of the two main Australian chiropractic associations between 30th June 2013 and 7th August 2013. The participants were asked to provide information on treatment choices for specific spinal musculoskeletal conditions.
280 respondents. Diversified manipulative technique was the first choice of treatment for most of the included conditions. Diversified was used significantly less in 4 conditions; cervical disc syndrome with radiculopathy and cervical central stenosis were more likely to be treated with Activator; flexion distraction technique was used almost as much as Diversified in the treatment of lumbar disc syndrome with radiculopathy and lumbar central stenosis. More experienced Australian chiropractors use more Activator and soft tissue therapy and less Diversified technique compared to their less experienced peers. The majority of responding chiropractors used ancillary procedures such as soft tissue techniques and exercise prescription in the treatment of spinal musculoskeletal conditions.
This survey provides information on commonly used treatment choices to the chiropractic profession. Treatment choices changed based on the region of disorder and whether neurological symptoms were present rather than with specific diagnoses. Diversified technique was the most commonly used spinal manipulative therapy, however, ancillary procedures such as soft tissue techniques and exercise prescription were also commonly utilised. This information may help direct future studies into the efficacy of chiropractic treatment for spinal musculoskeletal disorders.
Electronic supplementary material
The online version of this article (doi:10.1186/s12998-014-0033-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4193988  PMID: 25309722
Chiropractic; Technique systems; Manipulation; Manual therapy; Musculoskeletal; Treatment; Prevalence
23.  Domestic water carrying and its implications for health: a review and mixed methods pilot study in Limpopo Province, South Africa 
Environmental Health  2010;9:52.
Lack of access to safe water remains a significant risk factor for poor health in developing countries. There has been little research into the health effects of frequently carrying containers of water. The aims of this study were to better understand how domestic water carrying is performed, identify potential health risk factors and gain insight into the possible health effects of the task.
Mixed methods of data collection from six were used to explore water carrying performed by people in six rural villages of Limpopo Province, South Africa. Data was collected through semi-structured interviews and through observation and measurement. Linear regression modelling were used to identify significant correlations between potential risk factors and rating of perceived exertion (RPE) or self reported pain. Independent t-tests were used to compare the mean values of potential risk factors and RPE between sub-groups reporting pain and those not reporting pain.
Water carrying was mainly performed by women or children carrying containers on their head (mean container weight 19.5 kg) over a mean distance of 337 m. The prevalence of spinal (neck or back) pain was 69% and back pain was 38%. Of participants who carried water by head loading, the distance walked by those who reported spinal pain was significantly less than those who did not (173 m 95%CI 2-343; p = 0.048). For head loaders reporting head or neck pain compared to those who did not, the differences in weight of water carried (4.6 kg 95%CI -9.7-0.5; p = 0.069) and RPE (2.5 95%CI -5.1-0.1; p = 0.051) were borderline statistically significant. For head loaders, RPE was significantly correlated with container weight (r = 0.52; p = 0.011) and incline (r = 0.459; p = 0.018)
Typical water carrying methods impose physical loading with potential to produce musculoskeletal disorders and related disability. This exploratory study is limited by a small sample size and future research should aim to better understand the type and strength of association between water carrying and health, particularly musculoskeletal disorders. However, these preliminary findings suggest that efforts should be directed toward eliminating the need for water carrying, or where it must continue, identifying and reducing risk factors for musculoskeletal disorders and physical injury.
PMCID: PMC2939590  PMID: 20796292
24.  High force reaching task induces widespread inflammation, increased spinal cord neurochemicals and neuropathic pain 
Neuroscience  2008;158(2):922-931.
Repetitive strain injuries (RSI), which include several musculoskeletal disorders and nerve compression injuries, are associated with performance of repetitive and forceful tasks. In this study, we examined the effects of performing a voluntary, moderate repetition, high force (MRHF; 9 reaches/min; 60% maximum pulling force) task for 12 weeks on motor behavior and nerve function, inflammatory responses in forearm musculoskeletal and nerve tissues and serum, and neurochemical immunoexpression in cervical spinal cord dorsal horns. We observed no change in reach rate, but reduced voluntary participation and grip strength in week 12, and increased cutaneous sensitivity in weeks 6 and 12, the latter indicative of mechanical allodynia. Nerve conduction velocity (NCV) decreased 15% in the median nerve in week 12, indicative of low-grade nerve compression. ED-1 cells increased in distal radius and ulna in week 12, and in the median nerve and forearm muscles and tendons in weeks 6 and 12. Cytokines IL-1α, IL-1β, TNF-α, and IL-10 increased in distal forearm bones in week 12, while IL-6 increased in tendon in week 12. However, serum analysis revealed only increased TNF-α in week 6 and macrophage inflammatory protein 3a (MIP3a) in weeks 6 and 12. Lastly, Substance P and neurokinin-1 were both increased in weeks 6 and 12 in the dorsal horns of cervical spinal cord segments. These results show that a high force, but moderate repetition task, induced declines in motor and nerve function as well as peripheral and systemic inflammatory responses (albeit the latter was mild). The peripheral inflammatory responses were associated with signs of central sensitization (mechanical allodynia and increased neurochemicals in spinal cord dorsal horns).
PMCID: PMC2661572  PMID: 19032977
spinal cord; macrophages; cytokines; musculoskeletal disorder; nerve injury; repetitive strain injury
25.  Effect of Preexisting Musculoskeletal Diseases on the 1-Year Incidence of Fall-related Injuries 
People who have chronic diseases, as well as gait imbalance or psychiatric drug use, may be susceptible to injuries from falls and slips. The purpose of this study was to evaluate the effect of musculoskeletal diseases on incidental fall-related injuries among adults in Korea.
We analyzed data from the 4th Korea National Health and Nutrition Examination Survey (2007-2009), which are national data obtained by a rolling survey sampling method. The 1-year incidence of fall-related injuries was defined by health service utilization within the last year due to injury occurring after a slip and fall, and musculoskeletal diseases included osteoarthritis, rheumatoid arthritis, osteoporosis, and back pain. To evaluate the effects of preexisting musculoskeletal diseases, adults diagnosed before the last year were considered the exposed group, and adults who had never been diagnosed were the unexposed group.
The weighted lifetime prevalence of musculoskeletal disease was 32 540 per 100 000 persons. Musculoskeletal diseases were associated with a higher risk of fall-related injury after adjustment for sex, age, residence, household income, education, occupation, visual disturbance, paralysis due to stroke, and medication for depression (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.03 to 1.93). As the number of comorbid musculoskeletal diseases increased, the risk of fall-induced injuries increased (p-value for trend <0.001). In particular, patients who had any musculoskeletal condition were at much higher risk of recurrent fall-related injuries (OR, 6.20; 95% CI, 1.06 to 36.08).
One must take into account the risk of fall-related injuries and provide prevention strategies among adults who have musculoskeletal diseases.
PMCID: PMC3469810  PMID: 23091653
Arthritis; Osteoporosis; Back pain; Accidental falls; Wounds and injuries

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