Elimination of a pressure ulcer with electrical stimulation--a case study

Pressure ulcers, also called decubitus ulcers, are a common challenge of humanity and are exceptionally difficult to heal. They are wounds that are initiated by relatively short periods of pressure on the skin that blocks blood circulation causing the skin and underlying tissues to die, leading to an open wound. Pressure release can prevent further tissue degeneration, and some ulcers heal and disappear by themselves. However, many pressure ulcers never heal and continue to grow in diameter and depth. By one year, such unhealing ulcers are referred to as chronic ulcers. Chronic ulcers frequently jeopardize the life of the patient due to infections that become increasingly deep until they invade bones and the circulatory system. We report on a patient with a chronic pressure ulcer at his coccyx prominence. Fourteen months after the ulcer had appeared, a surface pulse electromagnetic force (PEMF) stimulator was applied over T7-T8, 45 cm cephalic to the ulcer, as part of a nerve stimulation study. Although the ulcer had continued to grow both in diameter and depth for 14 months and showed no signs of healing, within 6 days of applying the PEMF stimulator, the ulcer began to heal and was fully eliminated after 3 months. We concluded that the electrical stimulation induced the healing of the pressure ulcer. The ulcer elimination is quite surprising due to the exceptionally low electric field-force being generated by the stimulator at a distance of 45 cm.

Morphine: axon regeneration, neuroprotection, neurotoxicity, tolerance, and neuropathic pain

Opioids have been used medicinally for millennia for their potent effects on nociception. However, the past 20 years have led to important insights into the influences and mechanisms of opioid actions, which are more extensive than merely analgesia, including human synthesis of opioids, critical roles of opioids during development and following nerve injury, and actions of different opiate alkaloids and their receptors. Due to the vast literature on opioids, the scope of this review has been limited to opioid actions in maintaining neuron viability during development, promoting neurological function following nerve injuries, in inflammation, disease and against ischemia; alleviating neuropathic pain; raising and lowering cellular immunity; and mechanisms modifying morphine tolerance.

Visualization of six unique morphological subpopulations of adult frog dorsal root ganglion neurons at the light microscopic level

Subpopulations of adult frog dorsal root ganglion (DRG) neurons respond to different physiological stimuli, and have unique biophysical and pharmacological properties. Two broad-based subpopulations of DRG neurons appear under phase optics, "large clear" and "small dark" neurons, while immunochemical and electrophysiological techniques allow identification of additional subpopulations. Nevertheless, most studies of DRG neurons involve randomly selected neurons. Under bright field illumination, we found dark and clear DRG neurons are distinctly different, with dark neurons composed of four subpopulations, each with unique numbers and distribution of bright rusty-colored cytoplasmic granules, and statistically significant difference in the soma diameter distribution. The clear neurons are granule-free, but the two subpopulations have statistically significant differences in soma size distributions. Thus, morphological criteria alone allow identification of six distinct subpopulations of DRG neurons in the light microscope, although further studies are required to determine whether they correspond to physiologically different subpopulations of sensory neurons.

A novel technique leading to complete sensory and motor recovery across a long peripheral nerve gap

Sensory nerve grafts are the [quot ]gold standard[quot ] for inducing neurological recovery in peripheral nerves with a gap. However, the effectiveness of sensory nerve grafts is variable, generally not leading to complete sensory and motor recovery, with good recovery limited to gaps shorter than 2 cm, and the extent of recovery decreasing with increasing graft length. An alternative technique using a conduit filled with pure fibrin to bridge a nerve gap leads to only limited neurological recovery. We tested the effectiveness of a novel nerve repair technique in which a 5-cm long radial nerve gap was repaired using two sural nerve graft surrounded by a collage tube filled with pure fibrin. By 1 1/2 years post surgery, the patient recovered complete sensory and motor function. In conclusion, this study suggests that the combination of pure fibrin surrounding sural nerve grafts is responsible for inducing the extensive neurological recovery induced by either pure fibrin or sural grafts alone. This technique is presently being tested in a clinical trial.

Morphological characterization of six subpopulations of adult human DRG neurons at the light microscopic level

Dorsal root ganglion (DRG) neurons are composed of physiologically distinct subpopulations, each responding to a different sensory stimulus. One can morphologically discriminate between two broad populations of adult rat and frog DRG neurons by their appearance under the light microscope. These groups are called large clear and small dark. However, additional subpopulations have not been identified by visual observation. Such identification requires application of immunochemistry or biophysical techniques. Although these are useful techniques, they do not allow the rapid discrimination of different neuron subpopulations, which would be useful for pharmacological studies on unique neuron subpopulations. Such experiments would be greatly facilitated if viable DRG neuron subpopulations could be identified based on their morphology at the light microscopic level. Just as for adult frog and rat DRG neurons, when adult human DRG neurons are observed under phase optics, two subpopulations can be seen, small dark and large light. However, under bright-field illumination, six distinct subpopulations can be distinguished based solely on morphological features. Five subpopulations contain rusty-colored cytoplasmic inclusions with different sized granules and differences in the size and density of the granule clusters, while one is granule-free. Analysis of the soma diameter distribution shows each of the six granule-containing and the non-granule-containing (clear) neuron subpopulations has a statistically significant difference in size distribution. We propose that neurons with different morphologies correspond to unique physiological subpopulations of DRG neurons. Experiments are underway using immunochemical techniques to determine whether neurons with the unique morphologies correspond with unique physiological functions.

Are there causal relationships between the development of the inflammatory diseases amyotrophic lateral sclerosis and asthma?

Amyotrophic lateral sclerosis (ALS) and asthma are inflammatory diseases. ALS is a fatal progressive, neurodegenerative disease with inflammation around the upper and lower motor neurons leading to their degeneration, muscle atrophy, paralysis, and death. Asthma is a chronic inflammatory disease with reversible airway obstruction and nonspecific airway hyper-reactivity. The local release of sensory neuropeptides from capsaicin-sensitive primary afferents causes motor neuron pathophysiology and airway inflammation and hyper-reactivity. While there is no cure for ALS, asthma is managed according to its symptoms and severity, to decrease the symptoms, improve pulmonary function, and reduce morbidity. To determine whether understanding asthma may provide insights into how to clinically deal with ALS, the authors examined the etiologies of ALS and asthma, and the factors that exacerbate the symptoms. Although no direct correlations were found, the similar multifactorial triggers, and the critical roles of neuronal inflammation, suggest that one or more exists.

Neuroprotection of adult human neurons against ischemia by hypothermia and alkalinization

Ischemia of intact dorsal root ganglia (DRG) in situ leads to massive neuron death due to ischemia-triggered secondary events, such as massive release of excitatory amino acids from the neurons, their excessive accumulation and activation of neuron NMDA and other receptors, acidification, and loss of calcium homeostasis. The present experiments tested whether hypothermia and alkalinization, separately or combined, provide neuroprotection against 1-4 hours of ischemia to the neurons within intact DRG acutely removed from organ donors. DRG under hypothermic (20-15 degrees C) or alkaline (pH 8.0-9.3) conditions yielded more viable neurons than DRG maintained under physiological conditions (37 degrees C/pH 7.4), 4.1-fold vs. 7.8-fold respectively, but, hypothermia and alkalinization combined (20 degrees C/pH 9.3) increased the yield of viable neurons 26-fold compared to DRG maintained under physiological conditions. These results show that combined hypothermia and alkalinization provide adult human DRG neurons significant neuroprotection against ischemia, and ischemia-induced causes of neuron death.

Advances in spinal cord repair techniques

Daily US accidents result annually in over 20,000 cases of traumatic spinal cord injury associated with complete and permanent paraplegias and quadriplegias frequently associated chronic pain. This amounts to new annual health care a costs of dollar 3.2 billion, and a total annual cost for all such individuals in the US of dollar 96 billion. Tens of thousands of additional people suffer lesser degrees of permanent debilitating lost spinal cord function. To help these people recover neurological functions, and simultaneously reduce the enormous suffering, and the associated medical expenses, requires developing techniques that induce the regeneration of lesioned adult human spinal cord axons. A number of techniques lead to varying degrees of axon regeneration and neurological recovery in the rat, but the recovery is invariably limited. While other approaches show potential, they have not led reliable neurological recovery. Most spinal cord repair techniques cannot be applied clinically because they require materials that are not FDA-approved. However, several FDA-approved materials are available that hold great promise for inducing axon regeneration, especially when used simultaneously. Here we review efforts to induce the regeneration of spinal cord axons, how what is known about promoting regeneration of axons across peripheral nerve gaps may be applied to repairing spinal cord lesions, and finally, how several readily available materials may induce axons to regenerate in the spinal cord and restore neurological function.

Promoting neurological recovery following a traumatic peripheral nerve injury

If a peripheral nerve is crushed, or if the nerve is cut and the ends sutured together soon after the lesion (anastomosed), neurological recovery is good. When a length of a peripheral nerve is destroyed, and anastomosis is not possible, the standard surgical repair technique is to graft a length/s of sensory nerve from the patient, into the gap. For gaps 4 cm recovery is limited to non-existent. The limited recovery is because sensory nerves act as passive scaffolds for axon regeneration and do not actively promote axon regeneration. However, such grafts remain the [quot ]gold standard[quot ] for nerve repairs. New techniques are required that induce improved neurological recovery. This paper reviews current clinical and basic research techniques for inducing neurological recovery following traumatic peripheral nerve injuries.

Neuroprotection of spinal neurons against blunt trauma and ischemia

Each year in the Unites States there are over 10,000 new cases of para- and quadriplegia, and more than 100,000 cases of limited, but permanent, neurological losses. Many of these losses result from blunt trauma and ischemia to the spinal cord which leads to neuron death. Although blunt trauma directly kills neurons due to the physical trauma, over the subsequent 48 hours an even larger population of neurons dies due to secondary causes. One of leading triggers of this neuron death is ischemia due to the disruption of the blood circulation. Selective, but unavoidable, spinal cord ischemia occurs during thoracoabdominal surgery to repair aortic aneurysms. This ischemia leads to neuron death, functional neurological loss, and paraplegia in up to 33 per cent of the cases. Thus, both blunt trauma and induced ischemia have similar triggers of neuron death. To reduce the neurological losses resulting from ischemia mechanisms must be found to make spinal neurons more tolerant to ischemic insult and other secondary causes of neuron death. In this review we discuss mechanisms being developed, predominantly using animal models, to provide neuroprotection to prevent neurological losses following blunt trauma and during induced spinal cord ischemia. In parallel, our own experiments are looking at neuroprotective techniques using adult human neurons. We believe the optimal neuroprotective approach will involve the perfusion of the ischemic region of the spinal cord with a hypothermia solution containing a combination of pharmacological agents.