Transplantation of ß-endorphin neurons into the hypothalamus promotes immune function and restricts the growth and metastasis of mammary carcinoma.

Neurobehavioral stress has been shown to promote tumor growth and progression and dampen the immune system. In this study, we investigated whether inhibiting stress hormone production could inhibit the development of mammary carcinoma and metastasis in a rat model of breast carcinogenesis. To enhance ß-endorphin (BEP), the endogenous opioid polypeptide that boosts immune activity and decreases stress, we generated BEP neurons by in vitro differentiation from fetal neuronal stem cells and transplanted them into the hypothalami of rats subjected to breast carcinogenesis. BEP-transplanted rats displayed a reduction in mammary tumor incidence, growth, malignancy rate, and metastasis compared with cortical cells-transplanted rats. BEP neuron transplants also reduced inflammation and epithelial to mesenchymal transition in the tumor tissues. In addition, BEP neuron transplants increased peripheral natural killer (NK) cell and macrophage activities, elevated plasma levels of antiinflammatory cytokines, and reduced plasma levels of inflammatory cytokines. Antimetastatic effects along with stimulation of NK cells and macrophages could be reversed by treatment with the opiate antagonist naloxone, the ß-receptor agonist metaproterenol, or the nicotine acetylcholine receptor antagonist methyllycaconitine. Together, our findings establish a protective role for BEP against the growth and metastasis of mammary tumor cells by altering autonomic nervous system activities that enhance innate immune function.

Beta-endorphin neuronal cell transplant reduces corticotropin releasing hormone hyperresponse to lipopolysaccharide and eliminates natural killer cell functional deficiencies in fetal alcohol exposed rats.

BACKGROUND: Natural killer (NK) cell dysfunction is associated with hyperresponse of corticotropin releasing hormone (CRH) to immune challenge and with a loss of beta-endorphin (BEP) neurons in fetal alcohol exposed animals. Recently, we established a method to differentiate neural stem cells into BEP neurons using cyclic adenosine monophosphate (cAMP)-elevating agents in cultures. Hence, we determined whether in vitro differentiated BEP neurons could be used for reversing the compromised stress response and immune function in fetal alcohol exposed rats. METHODS: To determine the effect of BEP neuron transplants on NK cell function, we implanted in vitro differentiated BEP neurons into the paraventricular nucleus of pubertal and adult male rats exposed to ethanol or control in utero. The functionality of transplanted BEP neurons was determined by measuring proopiomelanocortin (POMC) gene expression in these cells and their effects on CRH gene expression under basal and after lipopolysaccaride (LPS) challenge. In addition, the effectiveness of BEP neurons in activating NK cell functions is determined by measuring NK cell cytolytic activity and interferon-gamma (IFN-gamma) production in the spleen and in the peripheral blood mononuclear cell (PBMC) following cell transplantation. RESULTS: We showed here that when these in vitro differentiated BEP neurons were transplanted into the hypothalamus, they maintain biological functions by producing POMC and reducing the CRH neuronal response to the LPS challenge. BEP neuronal transplants significantly increased NK cell cytolytic activity in the spleen and in the PBMC and increased plasma levels of IFN-gamma in control and fetal alcohol exposed rats. CONCLUSIONS: These data further establish the BEP neuronal regulatory role in the control of CRH and NK cell cytolytic function and identify a possible novel therapy to treat stress hyperresponse and immune deficiency in fetal alcohol exposed subjects.

Cyclic adenosine monophosphate differentiated beta-endorphin neurons promote immune function and prevent prostate cancer growth.

Pituitary adenylate cyclase-activating peptide (PACAP), a cAMP-activating agent, is highly expressed in the hypothalamus during the period when many neuroendocrine cells become differentiated from the neural stem cells (NSCs). Activation of the cAMP system in rat hypothalamic NSCs differentiated these cells into beta-endorphin (BEP)-producing neurons in culture. When these in vitro differentiated neurons were transplanted into the paraventricular nucleus (PVN) of the hypothalamus of an adult rat, they integrated well with the surrounding cells and produced BEP and its precursor gene product, proopiomelanocortin (POMC). Animals with BEP cell transplants demonstrated remarkable protection against carcinogen induction of prostate cancer. Unlike carcinogen-treated animals with control cell transplants, rats with BEP cell transplants showed rare development of glandular hyperplasia, prostatic intraepithelial neoplasia (PIN), or well differentiated adenocarcinoma with invasion after N-methyl-N-nitrosourea (MNU) and testosterone treatments. Rats with the BEP neuron transplants showed increased natural killer (NK) cell cytolytic function in the spleens and peripheral blood mononuclear cells (PBMCs), elevated levels of antiinflammatory cytokine IFN-gamma, and decreased levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in plasma. These results identified a critical role for cAMP in the differentiation of BEP neurons and revealed a previously undescribed role of these neurons in combating the growth and progression of neoplastic conditions like prostate cancer, possibly by increasing the innate immune function and reducing the inflammatory milieu.

Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism.

Dysfunctional neurotransmission within striatal networks is believed to underlie the pathophysiology of several neurological and psychiatric disorders. Nitric oxide (NO)-producing interneurons have been shown to play a critical role in modulating striatal synaptic transmission. These interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and may be regulated by DA receptor activation. In the current study, striatal NO efflux was measured in anesthetized male rats using an NO-selective electrochemical microsensor and the role of DA in modulating NO synthase (NOS) activity was assessed during electrical or chemical (bicuculline) stimulation of the substantia nigra (SN). Electrical stimuli were patterned to approximate the natural single spike or burst firing activity of midbrain DA neurons. Electrical stimulation of the SN at low frequencies induced modest increases in striatal NO efflux. In contrast, train stimulation of the SN robustly increased NO efflux in a stimulus intensity-dependent manner. NO efflux evoked by SN stimulation was similar in chloral hydrate- and urethane-anesthetized rats. The facilitatory effect of train stimulation on striatal NO efflux was transient and attenuated by systemic administration of the neuronal NOS inhibitor 7-nitroindazole and the nonselective NOS inhibitor methylene blue. Moreover, the increase in NO efflux observed during chemical and train stimulation of the SN was attenuated following systemic administration of the DA D(1/5) receptor antagonist SCH 23390. SCH 23390 also blocked NO efflux induced by systemic administration of the D(1/5) agonist SKF 81297. These results indicate that neuronal NOS is activated in vivo by nigrostriatal DA cell burst firing via a DA D(1/5)-like receptor-dependent mechanism.

Pseudoartrosis infectadas con perdida de substancia: progresos en su tratamiento / Infected pseudoarthrosis with substance loss: progress in its treatment

El presente trabajo fue efectuado en la división de traumatología del Hospital General de Agudos "Juan A. Fernández". Consta de 2 partes: una experimental y otra de clínica aplicada. La primera se basa en los estudios de Anatomía Quirúrgica y Microanatomía de 50 preparados y en el estudio de los principios mecánicos de estabilización del foco de pseudoartrosis mediante el uso de fijadores externos. La segunda se basa en las observaciones clínicas de 204 pacientes con pseudoartrosis infectada o supurada con pérdida de sustancia asistidos desde 04/1979 hasta 03/1985. En la parte experimental se han efectuado los estudios anatómicos sobre irrigación de la cresta ilíaca, sobre irrigación del peroné, sobre irrigación de la piel dadora de injertos cutáneos puros y finalmente sobre la irrigación intrínseca del colgajo del dorsal ancho. Los estudios biomecánicos comunes a todos los fijadores externos y en particular del fijador externo de Judet, del fijador externo tubular AO y del aparato de elongación de Wagner son analizados en detalle. En la parte clínica aplicada se señala la importancia del trípode clásico de tratamiento consistente en: a) resección completa de las estructuras tisulares óseas y blandas infectadas y necrosadas. b) estabilización del foco de pseudoartrosis y c) reparación de las pérdidas de sustancia ósea y/o tegumentaria con aporte biológico. Se señala la importancia de que la ecisión del hueso y partes blandas infectadas y necrosadas sea completa y precisa -ni insuficiente- para evitar fracasos o recidivas -ni excesiva- para disminuir o evitar los problemas subsiguientes de reconstrucción. Esta limpieza será efectuada desde la superficie a la profundidad, hasta haber escindido todos los tejidos infectados y necrosados, es decir, hay que resecar hasta superficies sangrantes. Se concluye que la estabilización del foco pseudoartrósico infectado con pérdida de sustancia es una indicación absoluta y que ella es idealmente lograda mediante el empleo de fijados externos. La experiencia recogida por los autores con el uso de fijador de Judet, del fijador tubular AO y del aparato de Wagner ha permitido demostrar la eficacia de los mismos en el tratamiento de la patología que nos ocupa... (TRUNCADO)

Pseudoartrosis infectadas con perdida de substancia: progresos en su tratamiento / Infected pseudoarthrosis with substance loss: progress in its treatment

El presente trabajo fue efectuado en la división de traumatología del Hospital General de Agudos "Juan A. Fernández". Consta de 2 partes: una experimental y otra de clínica aplicada. La primera se basa en los estudios de Anatomía Quirúrgica y Microanatomía de 50 preparados y en el estudio de los principios mecánicos de estabilización del foco de pseudoartrosis mediante el uso de fijadores externos. La segunda se basa en las observaciones clínicas de 204 pacientes con pseudoartrosis infectada o supurada con pérdida de sustancia asistidos desde 04/1979 hasta 03/1985. En la parte experimental se han efectuado los estudios anatómicos sobre irrigación de la cresta ilíaca, sobre irrigación del peroné, sobre irrigación de la piel dadora de injertos cutáneos puros y finalmente sobre la irrigación intrínseca del colgajo del dorsal ancho. Los estudios biomecánicos comunes a todos los fijadores externos y en particular del fijador externo de Judet, del fijador externo tubular AO y del aparato de elongación de Wagner son analizados en detalle. En la parte clínica aplicada se señala la importancia del trípode clásico de tratamiento consistente en: a) resección completa de las estructuras tisulares óseas y blandas infectadas y necrosadas. b) estabilización del foco de pseudoartrosis y c) reparación de las pérdidas de sustancia ósea y/o tegumentaria con aporte biológico. Se señala la importancia de que la ecisión del hueso y partes blandas infectadas y necrosadas sea completa y precisa -ni insuficiente- para evitar fracasos o recidivas -ni excesiva- para disminuir o evitar los problemas subsiguientes de reconstrucción. Esta limpieza será efectuada desde la superficie a la profundidad, hasta haber escindido todos los tejidos infectados y necrosados, es decir, hay que resecar hasta superficies sangrantes. Se concluye que la estabilización del foco pseudoartrósico infectado con pérdida de sustancia es una indicación absoluta y que ella es idealmente lograda mediante el empleo de fijados externos. La experiencia recogida por los autores con el uso de fijador de Judet, del fijador tubular AO y del aparato de Wagner ha permitido demostrar la eficacia de los mismos en el tratamiento de la patología que nos ocupa... (TRUNCADO)(AU)