RESUMEN
The importance and variability of pre-operative anaemia in cardiac surgical patients across the UK is not known, and there is debate about its association with patient outcomes. The Association of Cardiothoracic Anaesthetists carried out its first national audit on anaemia and transfusion, and analysed data from 19,033 patients operated on in 12 cardiac surgical centres between 2010 and 2012; 5895 (31%) had pre-operative anaemia. Centre-specific prevalence of anaemia varied from 23% to 45%; anaemia was associated with older patients, diabetes and surgical risk (EuroSCORE). Nevertheless, controlling for these factors, regional variation remained an independent effect (p < 0.001). Multivariable analysis demonstrated an independent association of anaemia with transfusion (odds ratio (95% confidence interval) 2.75 (2.55-2.95), p < 0.001), mortality (1.42 (1.18-1.71), p < 0.001) and hospital stay (geometric mean ratio (95% confidence interval) 1.15 (1.13-1.17), p < 0.001). Haemoglobin concentration per se was also independently associated with worse outcomes; a 10 g.l(-1) decrease in haemoglobin was associated with a 43% increase (95% confidence interval 40-46%) in the odds of transfusion and a 16% increase (95% confidence interval 10-22%) in the odds of mortality (both p < 0.001). This large UK-wide audit has demonstrated marked regional variation in both anaemia and transfusion, with a consistently high incidence of both. The independent association between pre-operative anaemia and worse outcomes in UK practice has also been confirmed, and robust prospective study of anaemia treatment before cardiac surgery is required; these data will assist in designing such trials.
Asunto(s)
Anemia/epidemiología , Procedimientos Quirúrgicos Cardíacos , Auditoría Médica , Anciano , Anciano de 80 o más Años , Transfusión Sanguínea , Procedimientos Quirúrgicos Cardíacos/mortalidad , Femenino , Hemoglobinas/análisis , Humanos , Incidencia , Tiempo de Internación , Masculino , Persona de Mediana EdadRESUMEN
Cardiac surgery and cardiopulmonary bypass are associated with haemodilution, activation of haemostasis and blood transfusion. We undertook a randomised controlled trial that included 53 patients in order to compare autotransfusion of residual cardiopulmonary bypass blood with residual blood concentrated using the novel Hemosep(®) device. There was no difference in patients' mean (SD) haemoglobin concentration after autotransfusion of unprocessed blood compared with Hemosep; 103.5 (10.2) g.l(-1) vs 106.2 (12.4) g.l(-1), respectively, p = 0.40. The mean (SD) change in haemoglobin concentration after autotransfusion was 5.9 (5.3) g.l(-1) in the control group compared with 4.9 (6.3) g.l(-1) in the Hemosep group, p = 0.545. Adjusted for baseline haemoglobin concentrations, the estimated mean (95% CI) difference in change in haemoglobin concentration (control vs Hemosep) was 0.57 (-2.65 to 3.79) g.l(-1), p = 0.72. This was despite Hemosep's reducing the weight of the blood from a mean (SD) of 778.7 (243.0) g to 607.3 (248.2) g, p < 0.001. The haemoglobin concentration in the processed blood increased from a mean (SD) of 87.0 (15.1) g.l(-1) to 103.7 (17.4) g.l(-1), p < 0.001. We conclude that Hemosep is capable of haemoconcentration when employed to process residual cardiopulmonary bypass blood, but that this is insufficient to increase patient haemoglobin.
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Transfusión de Sangre Autóloga/instrumentación , Puente Cardiopulmonar/métodos , Recuperación de Sangre Operatoria/instrumentación , Anciano , Recuento de Células Sanguíneas , Pruebas de Coagulación Sanguínea , Transfusión de Sangre Autóloga/métodos , Procedimientos Quirúrgicos Cardíacos/instrumentación , Procedimientos Quirúrgicos Cardíacos/métodos , Femenino , Hemodilución , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Recuperación de Sangre Operatoria/métodos , Recuento de Plaquetas , Resultado del TratamientoRESUMEN
Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.
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Proteínas Portadoras/metabolismo , Cuerpo Estriado/metabolismo , Citocinas/metabolismo , Enfermedades Neurodegenerativas/terapia , Fármacos Neuroprotectores/metabolismo , Sustancia Negra/metabolismo , Animales , Proteínas Portadoras/genética , Línea Celular , Citocinas/genética , Dependovirus/genética , Modelos Animales de Enfermedad , Terapia Genética , Vectores Genéticos/administración & dosificación , Masculino , Enfermedades Neurodegenerativas/inducido químicamente , Fármacos Neuroprotectores/farmacología , Oxidopamina , Ratas , Ratas Sprague-Dawley , Transducción GenéticaRESUMEN
Deep brain stimulation of the subthalamic nucleus (STN-DBS) is efficacious in treating the motor symptoms of Parkinson's disease (PD). However, the impact of STN-DBS on the progression of PD is unknown. Previous preclinical studies have demonstrated that STN-DBS can attenuate the degeneration of a relatively intact nigrostriatal system from dopamine (DA)-depleting neurotoxins. The present study examined whether STN-DBS can provide neuroprotection in the face of prior significant nigral DA neuron loss similar to PD patients at the time of diagnosis. STN-DBS between 2 and 4 weeks after intrastriatal 6-hydroxydopamine (6-OHDA) provided significant sparing of DA neurons in the SN of rats. This effect was not due to inadvertent lesioning of the STN and was dependent upon proper electrode placement. Since STN-DBS appears to have significant neuroprotective properties, initiation of STN-DBS earlier in the course of PD may provide added neuroprotective benefits in addition to its ability to provide symptomatic relief.
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Citoprotección/fisiología , Estimulación Encefálica Profunda/métodos , Dopamina/biosíntesis , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/prevención & control , Trastornos Parkinsonianos/terapia , Sustancia Negra/patología , Núcleo Subtalámico/fisiología , Animales , Muerte Celular/fisiología , Modelos Animales de Enfermedad , Masculino , Degeneración Nerviosa/patología , Inhibición Neural/fisiología , Trastornos Parkinsonianos/patología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/metabolismo , Núcleo Subtalámico/metabolismo , Núcleo Subtalámico/patología , Resultado del TratamientoRESUMEN
In this review we outline some relevant considerations with regards to the rat model of deep brain stimulation of the subthalamic nucleus (STN DBS). In order to optimize the rat STN DBS model in terms of predictive validity for the clinical situation we propose that the STN stimulation experimental design parameters in rodents should incorporate the following features: (i) stimulation parameters that demonstrate functional alleviation of symptoms induced by nigrostriatal dopamine (DA) denervation; (ii) stimulation duration that is relatively long-term and continuous; (iii) stimulation that is initiated at a time when the denervation status of the nigrostriatal system is known to be partial and progressing; (iv) stimulation current spread that is minimized and optimized to closely approximate the clinical situation; (v) the appropriate control conditions are included; and (vi) implantation to the STN target is verified post-mortem. Further research that examines the effect of long-term STN DBS on the neurophysiology and neurochemistry of STN circuitry is warranted. The rat model of functionally relevant long-term STN DBS provides a most favorable preclinical experimental platform in which to conduct these studies.
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Estimulación Encefálica Profunda , Modelos Animales de Enfermedad , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Animales , Neurotoxinas/toxicidad , Enfermedad de Parkinson/etiología , Ratas , Núcleo Subtalámico/anatomía & histología , Factores de TiempoRESUMEN
Studies in animals suggest that fetal neural grafts might restore lost neurological function in Parkinson's disease. In monkeys, such grafts survive for many months and reverse signs of parkinsonism, without attendant graft rejection. The successful and reliable application of a similar transplantation procedure to human patients, however, will require neural tissue obtained from human fetal cadavers, with demonstrated cellular identity, viability, and biological safety. In this report, human fetal neural tissue was successfully grafted into the brains of monkeys. Neural tissue was collected from human fetal cadavers after 9 to 12 weeks of gestation and cryopreserved in liquid nitrogen. Viability after up to 2 months of storage was demonstrated by cell culture and by transplantation into monkeys. Cryopreservation and storage of human fetal neural tissue would allow formation of a tissue bank. The stored cells could then be specifically tested to assure their cellular identity, viability, and bacteriological and virological safety before clinical use. The capacity to collect and maintain viable human fetal neural tissue would also facilitate research efforts to understand the development and function of the human brain and provide opportunities to study neurological diseases.
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Mesencéfalo/trasplante , Animales , Supervivencia Celular , Células Cultivadas , Cercopithecus , Feto , Congelación , Humanos , Masculino , Mesencéfalo/citología , Mesencéfalo/embriología , Mesencéfalo/enzimología , Preservación Biológica , Trasplante Heterólogo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Graft-induced dyskinesias (GIDs), side-effects found in clinical grafting trials for Parkinson's disease (PD), may be associated with the withdrawal of immunosuppression. The goal of this study was to determine the role of the immune response in GIDs. We examined levodopa-induced dyskinesias (LIDs), GID-like behaviors, and synaptic ultrastructure in levodopa-treated, grafted, parkinsonian rats with mild (sham), moderate (allografts) or high (allografts plus peripheral spleen cell injections) immune activation. Grafts attenuated amphetamine-induced rotations and LIDs, but two abnormal motor syndromes (tapping stereotypy, litter retrieval/chewing) emerged and increased with escalating immune activation. Immunohistochemical analyses confirmed immune activation and graft survival. Ultrastructural analyses showed increases in tyrosine hydroxylase-positive (TH+) axo-dendritic synapses, TH+ asymmetric specializations, and non-TH+ perforated synapses in grafted, compared to intact, striata. These features were exacerbated in rats with the highest immune activation and correlated statistically with GID-like behaviors, suggesting that immune-mediated aberrant synaptology may contribute to graft-induced aberrant behaviors.
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Discinesias/etiología , Discinesias/inmunología , Sinapsis/inmunología , Trasplante de Tejidos/efectos adversos , Adrenérgicos/toxicidad , Anfetamina , Animales , Antiparkinsonianos/efectos adversos , Conducta Animal , Modelos Animales de Enfermedad , Discinesias/patología , Antígenos de Histocompatibilidad Clase II/metabolismo , Levodopa/efectos adversos , Masculino , Microscopía Electrónica de Transmisión , Actividad Motora/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/cirugía , Ratas , Sinapsis/ultraestructura , Tirosina 3-Monooxigenasa/metabolismo , Tirosina 3-Monooxigenasa/ultraestructuraRESUMEN
Aging is the strongest risk factor for developing Parkinson's disease (PD). There is a preferential loss of dopamine (DA) neurons in the ventral tier of the substantia nigra (vtSN) compared to the dorsal tier and ventral tegmental area (VTA) in PD. Examining age-related and region-specific differences in DA neurons represents a means of identifying factors potentially involved in vulnerability or resistance to degeneration. Nitrative stress is among the factors potentially underlying DA neuron degeneration. We studied the relationship between 3-nitrotyrosine (3NT; a marker of nitrative damage) and DA transporters [DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT)] during aging in DA subregions of rhesus monkeys. The percentage of DA neurons containing 3NT increased significantly only in the vtSN with advancing age, and the vtSN had a greater percentage of 3NT-positive neurons when compared to the VTA. The relationship between 3NT and DA transporters was determined by measuring fluorescence intensity of 3NT, DAT and VMAT staining. 3NT intensity increased with advancing age in the vtSN. Increased DAT, VMAT and DAT/VMAT ratios were associated with increased 3NT in individual DA neurons. These results suggest nitrative damage accumulates in midbrain DA neurons with advancing age, an effect exacerbated in the vulnerable vtSN. The capacity of a DA neuron to accumulate more cytosolic DA, as inferred from DA transporter expression, is related to accumulation of nitrative damage. These findings are consistent with a role for aging-related accrual of nitrative damage in the selective vulnerability of vtSN neurons to degeneration in PD.
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Envejecimiento/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Degeneración Nerviosa/metabolismo , Sustancia Negra/metabolismo , Tirosina/análogos & derivados , Área Tegmental Ventral/metabolismo , Envejecimiento/patología , Animales , Citosol/metabolismo , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Macaca mulatta , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/patología , Sustancia Negra/patología , Tirosina/metabolismo , Área Tegmental Ventral/patología , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Transplantation of embryonic dopamine (DA) neurons has been tested as a therapy for Parkinson's disease. Most studies placed DA neurons into the striatum instead of the substantia nigra (SN). Reconstruction of this DA pathway could serve to establish a more favorable environment for control of DA release by grafted neurons. To test this we used cografts of striatum to stimulate growth of DA axons from embryonic SN that was implanted adjacent to the host SN in African green monkeys. Embryonic striatum was implanted at one of three progressive distances rostral to the SN. Immunohistochemical analysis revealed DA neuron survival and neuritic outgrowth from the SN grafts at 12-36 weeks after grafting. Each animal showed survival of substantial numbers of DA neurons. Most fibers that exited SN grafts coursed rostrally. Striatal grafts showed evidence of target-directed outgrowth and contained dense patterns of DA axons that could be traced from their origin in the SN grafts. A polarity existed for DA neurites that exited the grafts; that is, those seen caudal to the grafts did not appear to be organized into a directional outflow while those on the rostral side were arranged in linear profiles coursing toward the striatal grafts. Some TH fibers that reached the striatal grafts appeared to arise from the residual DA neurons of the SN. These findings suggest that grafted DA neurons can extend neurites toward a desired target over several millimeters through the brain stem and caudal diencephalon of the monkey brain, which favors the prospect of circuit reconstruction from grafted neurons placed into appropriate locations in their neural circuitry. Further study will assess the degree to which this approach can be used to restore motor balance in the nonhuman primate following neural transplantation.
Asunto(s)
Trasplante de Tejido Encefálico , Cuerpo Estriado/trasplante , Trasplante de Tejido Fetal , Sustancia Negra/trasplante , Animales , Biomarcadores/metabolismo , Cercopithecidae , Cuerpo Estriado/citología , Dopamina/metabolismo , Humanos , Masculino , Neuronas/citología , Neuronas/metabolismo , Sustancia Negra/citología , Sustancia Negra/embriologíaRESUMEN
Brain Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family of secreted growth factors. BDNF signaling is known to exert both chronic, pro-survival effects related to gene expression and protein synthesis ("canonical signaling"), and acute effects as a modulator of neurotransmission ("non-canonical signaling"). BDNF has received a great deal of attention for its role in neurodegenerative diseases including Huntington's Disease (HD), Alzheimer's Disease (AD), and Parkinson's Disease (PD) and has been extensively reviewed elsewhere in this regard (e.g., [1-6]). However aging-related changes in BDNF function and expression have been studied only rarely, with the majority of studies characterizing changes in structures such as the hippocampus and neocortex. In this review, we attempt to briefly summarize the extent of the existing literature on age-related BDNF changes, and discuss the relevance of these changes as a factor potentially impacting therapeutics in aged parkinsonian subjects.
RESUMEN
BACKGROUND: While acute kidney injury (AKI) alone is associated with increased mortality, the incidence of hospital admission with AKI among stable and exacerbating COPD patients and the effect of concurrent AKI at COPD exacerbation on mortality is not known. METHODS: A total of 189,561 individuals with COPD were identified from the Clinical Practice Research Datalink. Using Poisson and logistic regressions, we explored which factors predicted admission for AKI (identified in Hospital Episode Statistics) in this COPD cohort and concomitant AKI at a hospitalization for COPD exacerbation. Using survival analysis, we investigated the effect of concurrent AKI at exacerbation on mortality (n=36,107) and identified confounding factors. RESULTS: The incidence of AKI in the total COPD cohort was 128/100,000 person-years. The prevalence of concomitant AKI at exacerbation was 1.9%, and the mortality rate in patients with AKI at exacerbation was 521/1,000 person-years. Male sex, older age, and lower glomerular filtration rate predicted higher risk of AKI or death. There was a 1.80 fold (95% confidence interval: 1.61, 2.03) increase in adjusted mortality within the first 6 months post COPD exacerbation in patients suffering from AKI and COPD exacerbation compared to those who were AKI free. CONCLUSION: In comparison to previous studies on general populations and hospitalizations, the incidence and prevalence of AKI is relatively high in COPD patients. Coexisting AKI at exacerbation is prognostic of poor outcome.
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Lesión Renal Aguda/etiología , Lesión Renal Aguda/mortalidad , Progresión de la Enfermedad , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Tasa de Filtración Glomerular , Hospitalización , Humanos , Incidencia , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Reino UnidoRESUMEN
This commentary discusses the utility of behaviorally defined subpopulations of aged rodents as improved models of senescent memory dysfunction, the potential involvement of central norepinephrine systems in memory modulation, and the therapeutic outlook for age-related memory deficits.
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Envejecimiento/fisiología , Trastornos de la Memoria/fisiopatología , Envejecimiento/metabolismo , Animales , Modelos Animales de Enfermedad , Trastornos de la Memoria/metabolismo , Ratas , Proyectos de InvestigaciónRESUMEN
Literature on aging populations of rodents supports the intuitive view that significant functional variation exists among like-aged, elderly individuals: chronological age as a solitary measure is a poor indicator of biological age. In this report, we review a variety of studies which classify aged rodents based on genetic and/or behavioral similarities, in addition to chronological age, and have provided valuable neurobiological and physiological information on age-related changes which accompany functional impairments, or the lack of them. Beyond their descriptive value for gerontological research, these findings suggest ways in which biological aging can be manipulated to promote good function in aged individuals.
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Envejecimiento/fisiología , Roedores/fisiología , Envejecimiento/genética , Envejecimiento/psicología , AnimalesRESUMEN
Mammalian neural transplantation has recently been recognized to be a valuable technique for studying normal development and regeneration in the central nervous system. In addition, the ability of grafted neurons to reinnervate damaged regions of the host brain and to ameliorate some neuroendocrine deficits, cognitive disorders and motoric dysfunctions in young adult rodents has suggested that transplantation therapy may be effective in treating human neurodegenerative diseases and neurotransmitter deficiencies related to aging. It is of particular interest that initial studies of neuron transplants in aged rodents indicate that cholinergic, dopaminergic and noradrenergic neurons all integrate to some extent with the aged brain, and that the product of this graft-host interaction is improved behavioral performance of aged subjects. The present paper critically reviews the present domain of neural transplantation, its application to studies on the properties of the aged mammalian brain and discusses the possible therapeutic use of transplants in ameliorating transmitter-specific abnormalities associated with Parkinson's disease and Alzheimer's disease.
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Envejecimiento , Encéfalo/fisiología , Neuronas/trasplante , Médula Suprarrenal/trasplante , Animales , Encéfalo/cirugía , Línea Celular , Sistema Nervioso Central/trasplante , Trastornos del Conocimiento/cirugía , Feto , Predicción , Humanos , Hipogonadismo/cirugía , Mamíferos , Trastornos del Movimiento/cirugía , Neuronas/fisiología , Sistemas Neurosecretores/trasplante , Neurocirugia/métodos , Neurocirugia/tendencias , Procedimientos Neuroquirúrgicos , Nervios Periféricos/trasplante , Hormonas Liberadoras de Hormona Hipofisaria/fisiología , Vasopresinas/fisiología , VertebradosRESUMEN
Splenic noradrenergic innervation in young adult and aged Fischer 344 rats was examined using fluorescence histochemistry for catecholamines and high performance liquid chromatography with electrochemical detection (LCEC) for the quantitation of norepinephrine (NE). In young adult rats, abundant noradrenergic plexuses followed the vasculature and trabeculae into splenic white pulp. In aged rats, noradrenergic innervation was reduced in density and in overall intensity of fluorescence, and splenic NE levels were significantly lower. The relationship between diminished noradrenergic innervation and diminished immune responsiveness in aging mammals, while not clear on a causal level, is presented as a hypothesis for further testing.
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Bazo/inervación , Sistema Nervioso Simpático/crecimiento & desarrollo , Envejecimiento , Animales , Masculino , Microscopía Fluorescente , Norepinefrina/análisis , Ratas , Ratas Endogámicas F344 , Bazo/citología , Bazo/crecimiento & desarrollo , Sistema Nervioso Simpático/citologíaRESUMEN
Projections from the rat lateral entorhinal cortex (area 28-l) to the dentate gyrus were traced and then interpreted according to a parcellation scheme that recognized four cytoarchitectonic subdivisions of area 28-l: areas dorsolateral (dl), ventrolateral (vl), ventromedial (vm), and TR. Following lesions of area 28-l, anterograde degeneration was traced with the Fink-Heimer method. In parallel experiments iontophoretic injections of horseradish peroxidase (HRP) were made in the lateral perforant path terminal zone of the dentate molecular layer. Retrograde neuronal labeling patterns within area 28-l were charted following dorsal, midseptotemporal (mid ST), and ventral dentate injections. In two additional cases HRP was deposited in the ventral subiculum. Lesions of area dl (which lies entirely on the posterolateral cortex) produced terminal degeneration that was confined to the dorsal one-half of the dentate gyrus. Lesions involving primarily areas vl and vm (which lie on the posteroinferior cortex) caused a complementary pattern of degeneration; silver grains predominated in the ventral dentate gyrus. Injections of HRP into the outer dentate molecular layer labeled layer II neurons within area 28-l. Deposits of HRP in the dorsal one-third of the dentate gyrus labeled a rostrocaudal strip of neurons within the dorsal one-third of area dl; no other subdivisions of area 28-l contained labeling. After mid-ST deposits of HRP, a rostrocaudally oriented strip of labeled cells appeared in the ventral one-third of area dl. Mid-ST injections also labeled neurons in the caudolateral quadrant of area vl. Injection of HRP into the ventral dentate gyrus labeled neurons in the caudomedial quadrant of area vl as well as a few neurons in caudal area vm. No labeled cells were ever found in area dl following ventral dentate HRP deposits. Neurons within area TR were never retrogradely labeled from injections of HRP into the dentate perforant path zone. However, ventral subicular injections of HRP labeled a few cells in the posterior part of area TR, as well as hundreds of neurons throughout the rostrocaudal extent of area vl. The results indicate a highly organized innervation of the dentate gyrus by several subdivisions of area 28-l. In area dl, rostrocaudal strips of layer II neurons innervate distinct segments of the dorsal ST axis. The posterior half of areas vl and vm innervates the ventral half of the ST axis; a lateromedial gradient there corresponds to increasingly ventral terminations along the dentate ST axis.(ABSTRACT TRUNCATED AT 400 WORDS)
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Hipocampo/fisiología , Ratas/fisiología , Transmisión Sináptica , Animales , Gráficos por Computador , Vías Eferentes/anatomía & histología , Vías Eferentes/fisiología , Hipocampo/anatomía & histología , Peroxidasa de Rábano Silvestre , Masculino , Ratas Endogámicas , Terminología como AsuntoRESUMEN
Retrograde tracing experiments were performed to clarify the topographic projection from medial (area 28m) and intermediate (area 28i) divisions of the entorhinal cortex to the dentate gyrus. Pipets filled with horseradish peroxidase (HRP) were positioned by electrophysiologic guidance at one of several septotemporal (S-T) levels in the dentate molecular layer of anesthetized rats; the tracer was expelled iontrophoretically to minimize its spread. Retrograde labeling of neurons within areas 28m and 28i was analyzed in relation to cytoarchitectonic as well as spatial features of the region (obtained by histologic reconstruction). Regardless of the S-T level, ejections of HRP which were confined to the dentate gyrus labeled only layer II neurons of each area. Following septal pole ejections, labeled neurons were located in the posterolateral, extreme posterior, and posteromedial parts of both areas 28m and 28i. Mid S-T ejections produced not only a ventral, but also an anteromedial, shift in the location of entorhinal projection cells; no cells were labeled posterolaterally. After temporal dentate ejections labeled neurons occupied the most anteromedial part of these entorhinal areas. For both areas, but especially for area 28i, convergence of entorhinal efferents upon a single S-T level in the dentate gyrus occurred from neurons which lay in a dorsoventral (i.e., frontal), and to a lesser extent a rostrocaudal, plane. The efferent axes of both areas 28m and 28i thus appear to be curved and are therefore best described in three dimensions. The entorhinal axes begin in a posterodorsolateral location, wrap around the posterior cortical convexity, and end in an anteroventromedial position. The results provide a useful map for in situ exploration of entorhinodentate connections in the rat, emphasize the parallel innervation of the dentate gyrus by distinct entorhinal fiber systems, and reflect the importance of the S-T axis as a framework for interpreting hippocampal organization.
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Corteza Cerebral/anatomía & histología , Hipocampo/anatomía & histología , Sistema Límbico/anatomía & histología , Animales , Mapeo Encefálico , Vías Eferentes/anatomía & histología , Masculino , Ratas , Ratas EndogámicasRESUMEN
To enhance the current therapeutic benefit of dopamine (DA) neuron grafts in Parkinson's disease, strategies must be developed that increase both DA neuron survival and fiber outgrowth into the denervated striatum. Previous work in our laboratory has demonstrated that dopaminergic neurons grow to greater size when co-grafted with striatal cell suspensions and display extensive tyrosine hydroxylase-positive (TH+) projections, but no conclusion could be reached concerning enhancement of survival of grafted DA neurons. The aim of the present study was to characterize further the potential trophic effects of striatal co-grafts on grafted mesencephalic DA neuron survival. Unilaterally lesioned male Fischer 344 rats were grafted with either a suspension of mesencephalic cells or with both mesencephalic and striatal cell suspensions. Co-grafts were either mixed together or placed separately into the striatum. Lesioned rats receiving no graft served as controls. Rotational behavior was assessed following amphetamine challenge at 2 weeks prior to grafting and at 4 and 8 weeks following grafting. Only rats receiving co-grafts of nigral and striatal suspensions separated by a distance of 1 mm showed significant behavioral recovery from baseline rotational asymmetry. Both mixed and separate striatal co-grafts were associated with a doubling of DA neuron survival compared with solo mesencephalic grafts. In the mixed co-graft experiment, DA neurite branching appeared enhanced and TH-rich patches were observed, whereas with co-grafts that were separated, TH+ innervation of the intervening host striatum was increased significantly. These results provide the first evidence suggesting that nigral-striatal co-grafts, particularly those placed separately and in proximity to each other, increase both DA neuron survival and neurite extension from the mesencephalic component of the grafts.
Asunto(s)
Trasplante de Tejido Encefálico , Cuerpo Estriado/trasplante , Dopamina/fisiología , Trasplante de Tejido Fetal , Neuronas/trasplante , Animales , Antimetabolitos , Conducta Animal , Bromodesoxiuridina , Cuerpo Estriado/citología , Supervivencia de Injerto/fisiología , Masculino , Regeneración Nerviosa/fisiología , Neuronas/química , Neuronas/enzimología , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/cirugía , Ratas , Ratas Endogámicas F344 , Rotación , Sustancia Negra , Simpaticolíticos , Tirosina 3-Monooxigenasa/análisisRESUMEN
The neuroprotective properties of cyclosporin A (CsA) are mediated by its ability to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxin 3-nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20-30% reduction of striatal glutamic acid decarboxylase-immunoreactive (GAD-ir) neurons. A single treatment with CsA protected GAD-ir neurons from 3NP toxicity at lower (0.2 or 1.0 microM), but not at higher (5.0 microM) doses. Similar findings were seen when the cultures were treated twice with cyclosporin. In vivo experiments used the Lewis rat model of Huntington's disease (HD) in which a low 3NP dose was delivered subcutaneously through an osmotic minipump. Rats received unilateral or bilateral intrastriatal saline injections to disrupt the blood-brain barrier (BBB) and facilitate CsA reaching vulnerable neurons. In the first experiment, CsA treated 3NP-lesioned rats displayed significantly more dopamine-and adenosine-3;, 5;-monophosphate-regulated phosphoprotein (DARPP32-ir) neurons ipsilateral to BBB disruption compared to the contralateral intact striatum, indicating that disruption of the BBB maybe necessary for CsA's neuroprotective effects. In the second experiment, stereological counts of DARPP32-ir neurons revealed that CsA protected striatal neurons in a dose-dependent manner following bilateral disruption of the striatal BBB. Rats treated with the higher (15 or 20 mg/kg) but not lower (5 mg/kg) doses of CsA displayed greater numbers of DARRP32-ir striatal neurons relative to vehicle-treated 3NP-lesioned rats. Thus, under conditions in which CsA can gain access to striatal neurons, significant protection from 3NP toxicity is observed. Therefore, CsA or more lipophilic analogues of this compound, may be of potential therapeutic benefit by protecting vulnerable neurons from the primary pathological event observed in HD.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Ciclosporina/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Propionatos/toxicidad , Ratas/fisiología , Animales , Muerte Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Estriado/citología , Embrión de Mamíferos , Masculino , Nitrocompuestos , Ratas Endogámicas F344 , Ratas Endogámicas LewRESUMEN
Survival of embryonic dopamine (DA) neurons is extremely low (5-20%) following transplantation. Strategies to increase this survival are critical to the future of transplantation for Parkinson's disease. We demonstrate here that a factor(s) released from striatal oligodendrocyte-type 2 astrocytes (SO2A) greatly improves the survival and phenotype expression of mesencephalic DA neurons in culture while simultaneously decreasing the presence of apoptotic nuclear profiles, as detected by the TUNEL method and bisbenzamide/tyrosine hydroxylase double labeling. This SO2A-derived trophic factor(s) has minimal effects on glia and no effect on nondopaminergic mesencephalic neurons. The developmental period during which this SO2A trophic effect occurs (E14-18) coincides with the period when mesencephalic grafts are undergoing the highest rates of apoptosis, i.e., immediately following implantation. Therefore, SO2A-derived trophic factor(s) offers great potential for the augmentation of grafted DA neuron survival.