RESUMO
Sensory axons do not regenerate into or within the spinal cord because of the presence of the axon regeneration inhibitor chondroitin sulfate proteoglycan (CSPG) on activated astrocytes. In the peripheral nervous system, CSPG associated with denervated Schwann cells retards axon regeneration, but regeneration occurs because the balance of regenerating, inhibiting, and promoting factors favors regeneration. The present experiments were aimed at determining the mechanism by which Schwann cells inhibit adult human dorsal root ganglia (H-DRG) neuron growth cone elongation and substrate specificity, restricting the growth cones to Schwann cell membranes and inhibiting their growth onto a poly-l-lysine/laminin substrate. Neurites of H-DRG neurons free of soma contact with Schwann cells, or after the Schwann cell membranes' CSPG had been digested, were 11.1-fold longer than those of neurons in soma contact with untreated Schwann cells. Growth cones of DRG neuron somas without Schwann cell CSPG showed no outgrowth inhibition or substrate specificity. These results indicate that the Schwann cell CSPG influences act via contact with neuron somas but not growth cones. These results suggest that eliminating CSPG associated with Schwann cells within DRG in vivo will make the neurons' growth cones insensitive to the regeneration inhibitory influences of CSPG, allowing them to regenerate through the dorsal root entry zone and into and within the spinal cord, where they can establish appropriate and functional synaptic connections.
Assuntos
Condroitina ABC Liase/farmacologia , Proteoglicanas de Sulfatos de Condroitina/farmacologia , Gânglios Espinais/citologia , Neuritos/efeitos dos fármacos , Células de Schwann/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Adulto , Adesão Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/fisiologia , Células Cultivadas/ultraestrutura , Técnicas de Cocultura , Cones de Crescimento/fisiologia , Humanos , Modelos Neurológicos , Regeneração Nervosa/fisiologia , Neuritos/fisiologia , Células Receptoras Sensoriais/ultraestrutura , Especificidade por Substrato/efeitos dos fármacosRESUMO
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.
Assuntos
Estimulação Elétrica , Úlcera por Pressão/terapia , Adolescente , Humanos , Masculino , Indução de RemissãoRESUMO
Sensory nerve grafts are the "gold standard" 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.
Assuntos
Procedimentos Neurocirúrgicos/métodos , Nervo Radial/lesões , Nervo Radial/cirurgia , Nervo Sural/transplante , Adulto , Humanos , MasculinoRESUMO
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.
Assuntos
Gânglios Espinais/citologia , HumanosRESUMO
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.
Assuntos
Equilíbrio Ácido-Base , Gânglios Espinais/irrigação sanguínea , Hipotermia Induzida , Isquemia/prevenção & controle , Neurônios , Humanos , Concentração de Íons de Hidrogênio , Masculino , Fatores de TempoRESUMO
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 <2 cm neurological recovery is moderate, for gaps 2-4 cm recovery is generally poor, and 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 "gold standard" 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.
Assuntos
Traumatismos dos Nervos Periféricos , Nervos Periféricos/cirurgia , Humanos , Regeneração Nervosa , Procedimentos Neurocirúrgicos/métodos , Nervos Periféricos/fisiologiaRESUMO
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.
Assuntos
Regeneração Nervosa , Traumatismos da Medula Espinal/terapia , Axônios , Humanos , Neurologia/métodos , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/reabilitaçãoRESUMO
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% 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.
Assuntos
Hipotermia Induzida , Isquemia/prevenção & controle , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/terapia , Medula Espinal/irrigação sanguínea , Ferimentos não Penetrantes/terapia , Adulto , Animais , Cálcio/metabolismo , Morte Celular , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Isquemia/etiologia , Modelos Animais , Neurônios/efeitos dos fármacos , Neurotoxinas/metabolismo , Estresse Oxidativo , Paraplegia/etiologia , Paraplegia/prevenção & controle , Quadriplegia/etiologia , Quadriplegia/prevenção & controle , Traumatismos da Medula Espinal/complicações , Ferimentos não Penetrantes/complicaçõesRESUMO
In 1994 the government of Puerto Rico adopted a capitated managed health care system for the medically indigent. The new law has been implemented in most municipalities. A survey of children with special health care needs treated at a tertiary pediatric center under the capitated managed care system and the prior non-capitated system was analyzed using the Consumer Assessments of Health Plan Survey (CHAPS) instrument. One third of the patients who were under the new capitated managed care system were not satisfied with the medial care they were receiving. The parents of children with multidisciplinary conditions found it much more difficult to access care at the tertiary center. It took parents two years to learn to navigate within the capitated managed care system. Studies to measure outcome and health quality of children with special health care needs in capitated managed health care programs must be developed to learn how the potential benefits of managed care can be maximized and the potential harms minimized. The purpose of this study was to analyze the accessibility and satisfaction of caretakers of children with special health care needs under a capitated managed health care system.