Systematic review and meta-analysis of therapeutic hypothermia in animal models of spinal cord injury

Therapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously.In this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group.Systemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI -3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature.Systemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies

The node of Ranvier in CNS pathology.

Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K(+) channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders

Local cooling for traumatic spinal cord injury: outcomes in 20 patients and review of the literature: clinical article

Object. In this prospective study, the authors offered protocol-selected patients a combination of parenteral steroids, decompression surgery, and localized cooling to preserve viable spinal cord tissue and enhance functional recovery. Methods. After acquiring informed consent, the authors offered this regimen with localized deep cord cooling (dural temperature 6°C) to 20 patients with a neurologically complete spinal cord injury to begin within 8 hours of injury. After decompression, the cord was locally cooled through the intact dura using a suspended extradural saddle at the site of injury for up to 4 hours, during which time spinal fusion was performed. Sensation and motor function were evaluated directly after the injury and again over a year later. The patients were evaluated using the 2011 amendment to the American Spinal Injury Association (ASIA) Impairment Scale. Results. Eighty percent of the 20 patients (12 with cervical and 4 thoracic injuries) with an initial neurologically complete cord injury had some recovery of sensory or motor function. All patients initially had ASIA Grade A impairment. Of 14 patients with quadriplegia, 5 remained ASIA Grade A, 5 improved to ASIA Grade B, 3 to ASIA Grade C, and 1 to ASIA Grade D. The remaining 6 patients had suffered a thoracic spinal cord injury, and of these 2 remained ASIA Grade A, 1 recovered to ASIA Grade B, 2 to ASIA Grade C, and 1 ASIA Grade D. All considered, of 20 patients, 35% remained ASIA Grade A, 30% improved to ASIA Grade B, and 25% to ASIA Grade C. Impairment in 2 (10%) of 20 patients improved to ASIA Grade D. The mean improvement in neurological level of injury in all patients was 1.05, the mean improvement in motor level was 1.7, and the mean improvement in sensory level was 2.8. Two patients recovered the ability to walk, 2 could extend their legs, 5 could sense bladder fullness, and 3 had partial ability to void voluntarily. Four males recovered subnormal ability to have voluntary erection sufficient for limited sexual activity. Conclusions. The authors present here results of 20 patients with neurologically complete spinal cord injury treated with a combination of surgical decompression, glucocorticoid administration, and regional hypothermia. These patients experienced a better recovery than might have been expected had traditional forms of treatment been used. The benefit of steroid treatment for cord injury has been debated in the last decade, but the authors feel that research into the effects of cord cooling should be expanded. Given that the optimal neuroprotective temperature after acute trauma has not yet been defined, and may well be below that which is considered safely approachable through systemic cooling, methods that allow for the early attainment of such a temperature locally should be further explored. The results are encouraging enough to suggest the undertaking of controlled clinical trials of treatment using localized spinal cord cooling, where such treatment can be instituted within hours following injury

The effects of intracarotid methotrexate on the rhesus monkey.

The folic acid group: The discovery of Methotrexate and some of the other antimetabolic agents that are currently being used for the treatment of neoplastic disease is a long and colorful epic, beginning about thirty years ago. The development of these “folic acid analogs” was intimately tied in with the elucidation of one of the B complex vitamins, folic acid. Folic acid (pteroylglutamic acid) is found in many natural materials