Transplantation of Human Neural Progenitor Cells (NPC) into Putamina of Parkinsonian Patients: A Case Series Study, Safety and Efficacy Four Years after Surgery.

Individuals with Parkinson's disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients' dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients' neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson's disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513.

Genetic parameters and crossbreeding effects of fat deposition and fatty acid profiles in Iberian pig lines.

The aim of this study was to estimate the genetic and environmental parameters and crossbreeding effects on fatty acid and fat traits in the Iberian pig. Our final goal is to explore target selection traits and define crossbreeding strategies. The phenotypes were obtained under intensive management from 470 animals in a diallelic experiment involving Retinto, Torbiscal, and Entrepelado lines. The data set was composed of backfat thickness at the fourth rib (BFT), intramuscular fat (IMF) in the longissimus thoracis (LT), and the fatty acid profile for IMF and subcutaneous fat (SCF) traits. Data were analyzed through a Bayesian bivariate animal model by using a reparameterization of Dickerson's model. The results obtained showed an important genetic determinism for all traits analyzed with heritability ranging from 0.09 to 0.67. The common environment litter effect also had an important effect on IMF (0.34) and its fatty acid composition (0.06-0.53) at slaughter. The additive genetic correlation between BFT and IMF (additive genetic correlation [] = 0.31) suggested that it would be possible to improve lean growth independent of the IMF with an appropriate selection index. Furthermore, the high additive genetic correlation ( = 0.68) found between MUFA tissues would seem to indicate that either the LT or SCF could be used as the reference tissue for MUFA selection. The relevance of the crossbreeding parameters varied according to the traits analyzed. Backfat thickness at the fourth rib and the fatty acid profile of the IMF showed relevant differences between crosses, mostly due to line additive genetic effects associated with the Retinto line. On the contrary, those for IMF crosses were probably mainly attributable to heterosis effects. Particularly, heterosis effects were relevant for the Retinto and Entrepelado crosses (approximately 16% of the trait), which could be valuable for a crossbreeding system involving these lines.

Fetal homotransplants (ventral mesencephalon and adrenal tissue) to the striatum of parkinsonian subjects.

Fetal ventral mesencephalon and fetal adrenal tissue grafted to the caudate nucleus of four and three parkinsonian patients, respectively, have been shown to be an alternative treatment for the amelioration of the signs of the disease. The ventral mesencephalon patients had a significant amelioration of rigidity, bradykinesia, postural imbalance, gait disturbance, and facial expression. Three of these four patients have returned to work. The fatal adrenal group only showed amelioration of rigidity and bradykinesia. Though these patients are now able to perform their basic daily living activities, and one of them has renewed her household tasks, the other two have not yet been able to return to work. The differences observed between the ventral mesencephalon- and the fetal adrenal-transplanted patients may be related to the heterogeneity of their disease and/or the type of graft implanted. However encouraging our results may be, this experimental procedure obviously requires further studies, and should not be practiced outside of highly qualified clinical research centers.

Development of human neural transplantation.

The possibility of altering the course of Parkinson's disease by brain grafting is slowly becoming a reality through the efforts of many research groups worldwide. It has been shown that this procedure, as performed in high-level medical research centers, usually produces no permanent adverse effects and can effectively ameliorate parkinsonian signs in certain patients. This progress has served to reinforce our commitment to develop neural transplantation into an effective therapy to treat such a devastating neurodegenerative disease. We have summarized the most important events that have shaped the initial phase of this research. In the course of the last 4 years, considerable knowledge has been gained in the clinical neurosciences regarding the real potential of various brain grafting procedures in treating Parkinson's disease, their shortcomings, and their usefulness in carefully selected patients. There is still no consensus regarding the various fundamental aspects of human brain grafting in Parkinson's disease. Questions concerning surgical technique, candidate selection, the optimal brain regions for implantation, the optimal tissue for implantation, and the real usefulness of brain grafting must be addressed. The importance of the quality of adrenal medulla fragments for grafting, the requirement for immunosuppressors in fetal brain grafting, and the optimal fetal age and the amount of donor tissue for effective grafting are additional areas of concern. The potential of xenografting, preserved tissues, and genetically engineered cells for human brain grafting remain unanswered. The development of human neural transplantation is the responsibility and privilege of neurosurgery.

Botulinum toxin-A for the treatment of hemifacial spasm.

Management of hemifacial spasm can actually be done medically, surgically and with Botulinum-A Toxin. The Botulinum-A Toxin treatment locally injected into the involved facial muscles offers a useful alternative to medical and surgical therapy. The objective of this study was to evaluate the efficacy of Botulinum-A Toxin for the treatment of hemifacial spasm in those subjects for whom the presently available medical therapy is inadequate. A total of 28 individuals were enrolled in the clinical study. Patients were evaluated using the Fahn's blepharospasm rating and disability scales. Efficacy was assessed by evaluating changes from the baseline in eyelid spasm intensity, brow spasm intensity, eyelid force and facial spasm intensity. All 28 subjects with hemifacial spasm showed clinical improvement in relation to this baseline, which was statistically significant. The mean decrease from baseline at their follow-up examination was statistically significant for all subjects and for all measurements: eyelid spasm changed from 2.3 to 0.3 (p = 0.0001); brow spasm from 1.9 to 0.1 (p = 0.0001); facial spasm from 2.3 to 0.1 (p = 0.0001) and eyelid force from 0.9 to -0.1 (p = 0.0020). We concluded that Botulinum-A Toxin provides a significant therapeutic benefit to patients with hemifacial spasm, without the risk of disabling side effects.

[The first homotopic fetal homograft of the striatum in the treatment of Huntington's disease]. / Primer homotrasplante fetal homotópico de estriado para el tratamiento de la enfermedad de Huntington.

Fetal brain grafting has been used successfully in the restoration of striatal function in rat and non human primate models of Huntington's disease (HD). This is a report of the first clinical trial of this procedure applied to a 37 year old Mexican female with moderate to severe HD of 9 years evolution. The two striata from a 13 week-old human fetus were homotopically transplanted to 4 cavities in the ventricular wall of the right caudate nucleus. The months after surgery, her neurologic and neuropsychologic evaluations revealed the stabilization of many of her signs and most neuropsychologic parameters, a moderate improvement of her choreic movements, predominantly in the face, of her ability to define and express ideas in oral and written form, and of her articulatory agility, as well as of some activities of her daily life and social behavior. There was a slight deterioration of her gait and posture. Her saccadic system and optokinetic nystagmus, and her visuospatial and visuoperceptual functions were deteriorated.

Crossbreeding effects on pig growth and carcass traits from two Iberian strains.

An experiment of a 2×2 full diallelic cross between two contemporary Iberian pig strains (Retinto: RR, and Torbiscal: TT) was conducted to estimate the crossbreeding effects for growth and carcass traits. Phenotypic records were obtained under intensive management and consisted of two different data sets. The first set comprised growth traits until weaning and was collected at two different farms (6236 and 1208 records, respectively). Specific data included individual piglet weight at birth and at weaning at 28 days and average daily gain from birth to weaning at 28 days (ADG28) for both RR and TT and their reciprocal crosses. The second set comprised growth data from birth to slaughter (~340 days and ~160 kg) and carcass traits from 349 individuals (randomly) sampled at weaning from the first dataset. Data were analyzed through a Bayesian analysis by using a reparameterization of Dickerson's model that allowed estimation of the posterior distributions of the following crossbreeding effects: average maternal breed effect (gM), average paternal breed effect (gP) and individual heterosis (hI). Results showed that the relative magnitude of crossbreeding effects depends on the trait analyzed. Crosses where Torbiscal strain was used as mother (RT and TT) achieved the greatest performance for all growth traits at weaning, leading to remarkable gM effects. The most outstanding example is the case of ADG28 where the probability of relevance was one. In contrast, TR cross showed the greatest differences from RR cross for all growth at slaughter and carcass traits. These differences were mainly due to hI and gP crossbreeding parameters. In particular, the posterior mean of hI was more noticeable for live weight at slaughter, average daily gain at slaughter and carcass length, while gP was more relevant for hams (kg) and loins (kg) representing from 3% to10% of average performance of traits. Hence, growth traits at weaning did not reveal any notable advantage of the crossbreeding scheme because of the superiority of the Torbiscal strain with respect to its mothering ability and the small hI. However, results from growth and carcass traits at slaughter would support the implementation of a TR crossbred system. It would allow exploitation of both the gP of the Torbiscal strain and the hI between these two Iberian pig strains. Additionally, gP estimates and phenotypic differences between reciprocal crosses might suggest signs of the presence of paternal genetic imprinting in primal cuts traits.

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 Parkinson's disease (PD) 3 years after autologous adrenal medullary (AM)-to-caudate nucleus (CN) implantation, 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 rigidity, 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.

[Human fetal homograft to the nigrostriatal system for the treatment of Parkinson's disease]. / El homotrasplante fetal humano al sistema nigroestriado para el tratamiento de la enfermedad de Parkinson.

Four cases of transplant to the brain (striatum) of the ventral mesencephalic area (VMA) and three adrenal glands (A) to patients with Parkinson's disease are described as a new alternative for the improvement of this disease. The patients who received VMA showed a very significant improvement in the rigidity, bradykinesia, alterations in walking and posture, as well as the facial expression. Three of the four patients have returned to work. The group that received A tissue, showed a discreet improvement in the rigidity and bradykinesia, but none in the other signs of the disease. These patients are able to accomplish their daily needs, but two are unable to return to work. The differences which we observed between patients receiving VMA and A transplants, might be related to the heterogeneity of the disease, although we believe that the type of graft was responsible of these differences. Our results with the use of VMA, as well as that of other groups, are encouraging, although it is important to clearly establish that it is a procedure which is still in an experimental phase, requiring caution, and should only be practiced in highly qualified centers of clinical research.