Rebecca E. Franco-Bourland

Intraventricular Somatostatin-14, Arginine Vasopressin, and Oxytocin: Analgesic Effect in a Patient with Intractable Cancer Pain

The analgesic effect of intraventricular somatostatin-14 (SOM-14), arginine vasopressin (AVP), and oxytocin (OT) were tested in one terminally ill cancer patient with a diffuse mesothelioma suffering intractable continuous and incapacitating thoracic pain. SOM-14 reduced pain by 90% for 48 min; AVP reduced pain by 95% for 75 min, and OT reduced pain by 88% for 77 min. The only notable side effects were seen after the administration of AVP, which induced anesthesia and flaccid paralysis of the lower limbs, from which the patient fully recovered after 20 h.

Fetal striatal homotransplantation for Huntington's disease: First two case reports

Based on the successful use of fetal striatal brain grafting in the restoration of striatal function in rat and nonhuman primate models of Huntingtons disease, as well as on the evidence for the clinical potential of fetal brain grafting in the treatment of Parkinsons disease, homotopic fetal striatal homotransplantations were performed in two huntingtonians. Case 1 was a 37 year-old female with moderate to severe Huntingtons disease of 9 years evolution; case 2 was a 29 year-old male with mild Huntingtons disease of 5 years evolution. Using open microsurgery, each patient was implanted to the ventricular wall of the right caudate nucleus with both striata from a 13 week-old and a 12 week-old human fetus, respectively. Since surgery both patients were kept on cyclosporine A. Surgery produced no damaging effect to either patient. The time course of the neurological progression of their disease, spanning 33 months for case 1, and 16 months for case 2, reveal that the disease in both patients has progressed more slowly in relation to their preoperative state. Although presently it is not possible to determine to what extent, surgery has modified the course of their disease, or if it will continue to have an effect on it, these surgeries represent the first step towards the development of brain grafting for Huntingtons disease.

Development of post-traumatic cysts in the spinal cord of rats-subjected to severe spinal cord contusion.

To study the development of post-traumatic spinal cord (SC) cysts, and their fine anatomic characteristics, rats were subjected to severe SC contusion. Specimens were analyzed from day 1 to 1 year post-injury. Using conventional light, and transmission and scanning electron microscopy, three stages were typified, namely: necrosis, repair, and stability. The final cell composition and thickness of the cyst walls were not uniform. Astrocytes, fibroblasts, ependymal cells, and collagen fibers were the main constituents. Chronic inflammatory cells were also observed. The neuropathologic characterization of posttraumatic SC cysts could be useful in planning strategies for SC reconstruction at different times post-injury.

Glutathione monoethyl ester improves functional recovery, enhances neuron survival, and stabilizes spinal cord blood flow after spinal cord injury in rats.

Secondary damage after spinal cord (SC) injury remains without a clinically effective drug treatment. To explore the neuroprotective effects of cell-permeable reduced glutathione monoethyl ester (GSHE), rats subjected to SC contusion using the New York University impactor were randomly assigned to receive intraperitoneally GSHE (total dose of 12 mg/kg), methylprednisolone sodium succinate (total dose of 120 mg/kg), or saline solution as vehicle. Motor function, assessed using the Basso-Beattie-Bresnahan scale for 8 weeks, was significantly better in GSHE (11.2+/-0.6, mean+/-S.E.M., n=8, at 8 weeks) than methylprednisolone (9.3+/-0.6) and vehicle (9.4+/-0.7) groups. The number of neurons in the red nuclei labeled with FluoroRuby placed caudally to the injury site was significantly higher in GSHE (158+/-9.3 mean+/-S.E.M., n=4) compared with methylprednisolone (53+/-14.7) and vehicle (46+/-16.4) groups. Differences in the amount of spared SC tissue at the epicenter and neighboring areas were not significant among experimental groups. In a second series of experiments, using similar treatment groups (n=6), regional changes in microvascular SC blood flow were evaluated for 100 min by laser-Doppler flowmetry after clip compression injury. SC blood flow fell in vehicle-treated rats 20% below baseline and increased significantly with methylprednisolone approximately 12% above baseline; changes were not greater than 5% in rats given GSHE. In conclusion, GSHE given to rats early after moderate SC contusion/compression improves functional outcome and red nuclei neuron survival significantly better than methylprednisolone and vehicle, and stabilizes SC blood flow. These results support further investigation of reduced glutathione supplementation after acute SC injury for future clinical application.

Chapter 66 Neural transplantation (auto-adrenal, fetal nigral and fetal adrenal) in Parkinson's disease: the Mexican experience

Publisher Summary This chapter examines neural transplantation in Parkinsons disease (PD). In the study described in the chapter, 34 male and 8 female PD patients were selected for surgery. They had at least 3 of the 4 major PD symptoms, a Unified Parkinsonism Rating Scale (UPRS) score of less than 120 points in the “off” condition, a 50% response to L-dopa treatment for at least 3 hours, and a respiratory restriction because of rigidity during “off” of less than 40%. Using the same surgical technique in all cases, 39 patients received grafts to the right caudate nucleus (CN) and 3 to the left caudate, because of right sided predominance of the disease. An Ommaya-like reservoir was placed in 15 patients for ventricular fluid sampling. The statistical analyses of the clinical data were done with the Students paired t test, the Wilcoxons test for paired samples, and Rankits normal order statistics. Neuropsychological data were analyzed using the Mann–Whitney U-test. Biochemical data were analyzed using students t-test, students paired t-test, and the analysis of variance (ANOVA) test. Biochemical assessments led to the identification of a neurite outgrowth promoting activity (NOPA).

Lipid peroxidation by nitric oxide supplements after spinal cord injury: effect of antioxidants in rats

To determine the extent to which exogenous nitric oxide (NO) might affect hemodynamics and/or increase oxidative damage after acute spinal cord (SC) injury, rats were submitted to SC contusion, and given a NO donor or NO precursor. Intravenous isosorbide dinitrate (10 microg/kg per min) or L-arginine (300 mg/kg per 23 h) showed a tendency to increase lipid peroxidation (LP), although without reaching significance compared to non-treated injured rats 24 h post-injury, and without affecting mean arterial pressure and heart rate importantly. LP due to injury and exogenous NO was significantly inhibited by the co-administration of a cocktail of antioxidants (12 mg/kg superoxide dismutase mimetic, 27000 U/kg catalase, and 12 mg/kg glutathione), but less effectively for the injury-L-arginine condition. These results demonstrate that in order to further test the potential neuroprotective effect of NO enhancing reagents after SC injury, antioxidants must be included in the treatment scheme.

Chromogranin a immunoreactivity in human cerebrospinal fluid: Properties, relationship to noradrenergic neuronal activity, and variation in neurologic disease

Although measurement of chromogranin A in the bloodstream is of value in sympathoadrenal investigations, little is systematically known about chromogranin A in cerebrospinal fluid, despite substantial knowledge about its occurrence and distribution in brain. We therefore applied a homologous human chromogranin A radioimmunoassay to cerebrospinal fluid, in order to evaluate the properties and stability of cerebrospinal fluid chomogranin A, as well as its relationship to central noradrenergic neuronal activity, to peripheral (plasma) chromogranin A, and to disease states such as hypertension, renal failure and Parkinsonism. Authentic, physically stable chromogranin A immunoreactivity was found in cerebrospinal fluid (at 37-146 ng/ml; mean, 87.0 +/- 6.0 ng/ml in healthy subjects), and several lines of evidence (including 3.39 +/- 0.27-fold higher chromogranin A in cerebrospinal fluid than in plasma) indicated that it originated from a local central nervous system source, rather than the periphery. Cerebrospinal fluid chromogranin A values were not influenced by administration of effective antihypertensive doses of clonidine or propranolol, and were not related to the cerebrospinal fluid concentrations of norepinephrine, methoxyhydroxyphenylglycol, or dopamine-beta-hydroxylase; thus, cerebrospinal fluid chromogranin A was not closely linked to biochemical or pharmacologic indices of central noradrenergic neuronal activity. Cerebrospinal fluid chromogranin A was not changed (P > 0.1) in essential hypertension (84.2 +/- 14.0 ng/ml) or renal failure (72.2 +/- 13.4 ng/ml), despite a marked (7.1-fold; P < 0.001) increase in plasma chromogranin A in renal failure, and a modest (1.5-fold; P = 0.004) increase in plasma chromogranin A in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Transitory expression of NADPH diaphorase (NOS) in axonal swellings after spinal cord injury.

TO investigate the sites of nitric oxide synthase (NOS) expression after a spinal cord (SC) injury, NADPH-d diaphorase histochemistry was performed in the SC of adult rats sacrificed at different times from 1h to 90 days after both SC contusion or transection. NOS could first be seen 12h after injury in axonal swellings (AS) (club shaped structures at the tip of damage axons, associated with tissue destruction). NOS expression reached a maximum 3 days after injury, and gradually disappeared after 7 days. Finally, AS collapsed leaving behind micro-cysts. NOS expression and the consequent production of nitric oxide could be involved in the pathophysiology of the secondary damage, and/or could reflect a failed attempt for axonal regeneration

Autologous adrenal medullary, fetal mesencephalic, and fetal adrenal brain transplantation in Parkinson's disease: a long-term postoperative follow-up.

We report on the clinical status of 5 patients with Parkinsons disease (PD) 3 years after autologous adrenal medullary (AM)-to-caudate nucleus (CN) implanfion, and of 2 PD patients, 2 years after fetal ventral mesencephalon (VM)- and fetal adrenal (A)-to-CN homotransplantation. Current clinical evaluation of 4 of the AM grafted patients revealed sustained bilateral amelioration of their PD signs, most notably of rgidity, postural imbalance and gait disturbances, resulting in a substantial improvement in their quality of life. the disease-related dystonia of one of them disappeared only 2 years after surgery. The levodopa requirements of 2 of these patients and the anticholinergic therapy of another have been reduced. In agreement with the satisfactory clinical evaluation of these 4 patients, their neuropsychological and electrophysiological improvements, initially registered 3 months after surgery, have been maintained for 3 years. After 1 year of significant recovery, the 5th patient of this group has almost returned to her preoperative state. The 2 homotransplanted patients also showed sustained bilateral improvement of their PD signs. Two years after surgery, the most improved signs of the fetal VM case were rigidity, bradykinesia, postural imbalance, gait disturbances and facial expression. The fetal A case has only shown amelioration of rigidity and bradykinesia. Neither of them has shown significant neuropsychological changes. Their current levodopa requirements are less than before surgery. The improvements shown here by PD patients after brain tissue grafts go beyond those obtained using any other therapeutic approach, when levodopa fails. Although more studies and the development of these procedures are obviously required, these initial human trials appear to be resisting the test of time.

Neuroprotection of completely lacerated spinal cord of adult rats by homotopic and heterotopic transplantation

To evaluate the neuroprotective effect of transplants placed in the lesion zone after a complete spinal cord (SC) laceration, two independent series of experiments were carried out. In the first, allogeneic or xenogeneic fetal SC was transplanted into the gaps of the damaged lower thoracic SC of adult rats. In the transplanted rats the incidence of life-threatening complications was reduced, and the survival rate was increased compared with the control group (lesion, without implant). Histological examination showed less damage to the neighboring SC parenchyma in the transplanted rats. The measurement of this neuroprotective effect was made in a second series of experiments. Using the same model of SC injury, allogeneic fetal SC, autologous peripheral nerve and/or adipose tissue were implanted. Rats with implants of Gelfoam and damaged rats without implants were the controls. The implanted rats of all groups, including the Gelfoam group, showed a better survival rate than the nonimplanted rats. Significantly less damage to the neighboring SC parenchyma was measured in implanted rats with any of the live tissues tested compared with non-implanted rats, although no significant differences were observed between the Gelfoam group and the nonimplanted rats. Histological evidence of tissue implant survival was observed in all corresponding groups. It is concluded that the transplanted tissues tested here have a neuroprotective effect, possibly by acting as a buffer to neurotoxic substance(s) released by the stumps, and/or by exerting trophic effect(s) on the host.