RESUMEN
BACKGROUND: Patients experiencing large thermal injuries are susceptible to opportunistic infections that can delay recovery and lead to sepsis. Dendritic cells (DC) are important for the detection of pathogens and activation of the innate and acquired immune responses. DCs are significantly decreased in burn patients early after injury, and the development of sepsis is associated with persistent DC depletion. In a murine model of burn wound infection, the enhancement of DCs after injury by treatment with the DC growth factor Fms-like tyrosine kinase-3 ligand (FL) enhances neutrophil migration to infection, improves bacterial clearance, and increases survival in a DC-dependent manner. FL expands the production of both conventional DCs (cDC) and plasmacytoid DCs (pDC). It has been established that cDCs are required for some of the protective effects of FL after burn injury. This study was designed to determine the contribution of the pDC subset. METHODS: Mice were subjected to full-thickness scald burns under deep anesthesia and were provided analgesia. pDCs were depleted by injection of anti-plasmacytoid dendritic cell antigen-1 antibodies. Survival, bacterial clearance, and neutrophil responses in vivo and in vitro were measured. RESULTS: Depletion of preexisting pDCs, but not FL-expanded pDCs, abrogated the beneficial effects of FL on survival, bacterial clearance, and neutrophil migration in response to burn wound infection. This requisite role of pDCs for FL-mediated enhancement of neutrophil migratory capacity is not due to direct effects of pDCs on neutrophils. cDCs, but not pDCs, directly increased neutrophil migratory capacity after co-culture. CONCLUSIONS: The protective effects of FL treatment after burn injury are mediated by both pDCs and cDCs. Pharmacological enhancement of both DC subtypes by FL is a potential therapeutic intervention to enhance immune responses to infection and improve outcome after burn injury.
Asunto(s)
Quemaduras/inmunología , Células Dendríticas/inmunología , Proteínas de la Membrana/metabolismo , Neutrófilos/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/fisiología , Sepsis/inmunología , Animales , Quemaduras/microbiología , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Activación NeutrófilaRESUMEN
Adequate wound healing is vital for burn patients to reduce the risk of infections and prolonged hospitalization. Dendritic cells (DCs) are antigen presenting cells that release cytokines and are central for the activation of innate and acquired immune responses. Studies have showed their presence in human burn wounds; however, their role in burn wound healing remains to be determined. This study investigated the role of DCs in modulating healing responses within the burn wound. A murine model of full-thickness contact burns was used to study wound healing in the absence of DCs (CD11c promoter-driven diphtheria toxin receptor transgenic mice) and in a DC-rich environment (using fms-like tyrosine kinase-3 ligand, FL- a DC growth factor). Wound closure was significantly delayed in DC-deficient mice and was associated with significant suppression of early cellular proliferation, granulation tissue formation, wound levels of TGFß1 and formation of CD31+ vessels in healing wounds. In contrast, DC enhancement significantly accelerated early wound closure, associated with increased and accelerated cellular proliferation, granulation tissue formation, and increased TGFß1 levels and CD31+ vessels in healing wounds. We conclude that DCs play an important role in the acceleration of early wound healing events, likely by secreting factors that trigger the proliferation of cells that mediate wound healing. Therefore, pharmacological enhancement of DCs may provide a therapeutic intervention to facilitate healing of burn wounds.
Asunto(s)
Quemaduras , Proliferación Celular/fisiología , Células Dendríticas/fisiología , Tejido de Granulación , Neovascularización Fisiológica/fisiología , Cicatrización de Heridas/fisiología , Adyuvantes Inmunológicos/farmacología , Animales , Antígeno CD11c , Proliferación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Masculino , Proteínas de la Membrana/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Neovascularización Fisiológica/efectos de los fármacos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta , Regiones Promotoras Genéticas , Factor de Crecimiento Transformador beta1/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28-49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABA(A) receptors with open Cl(-) channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs.
Asunto(s)
Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Espinas Dendríticas/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Memoria a Corto Plazo/efectos de los fármacos , Factores de Edad , Animales , Espinas Dendríticas/patología , Giro Dentado/efectos de los fármacos , Dopamina/metabolismo , Extinción Psicológica/efectos de los fármacos , Masculino , Trastornos de la Memoria/fisiopatología , Núcleo Accumbens/efectos de los fármacos , Olanzapina , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , TiempoRESUMEN
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.
Asunto(s)
Benzodiazepinas/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Recompensa , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Factores de Edad , Animales , Animales Recién Nacidos , Benzamidas/farmacocinética , Benzazepinas/farmacología , Peso Corporal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Dopamina/metabolismo , Antagonistas de Dopamina/farmacocinética , Estudios de Seguimiento , Masculino , Olanzapina , Unión Proteica/efectos de los fármacos , Ratas , Ratas Long-Evans , Tritio/farmacocinéticaRESUMEN
While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.
Asunto(s)
Adaptación Fisiológica/fisiología , Neuronas Dopaminérgicas/fisiología , Morfina/farmacología , Neuronas/fisiología , Transactivadores/fisiología , Área Tegmental Ventral/fisiología , Adaptación Fisiológica/efectos de los fármacos , Adolescente , Adulto , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Transcripción , Área Tegmental Ventral/efectos de los fármacos , Adulto JovenRESUMEN
The aim of this pilot study was to determine the baseline state of oxidative stress indices in patients with Parkinson's disease (PD). Peripheral blood samples of 15 PD subjects were analyzed and compared with ten age matched healthy controls. Patients with PARK2 mutations were also compared with PD patients without mutations. There was significant increase in malondialdehyde content and superoxide-dismutase (SOD) activity in peripheral blood parameters in PD patients (p < 0.05) in comparison to controls. These findings suggest an important role of oxidative stress in Parkinson's disease evolution and progress. No changes were observed in glutathione peroxidase and nitric oxide levels. We found significant correlation between SOD activity and lipid peroxidation when the biochemical data was further analyzed. In addition, significant increase in the levels of SOD among the PD patients with PARK2 mutations was observed, which can be ascribed to chronic oxidative stress induced by PARK2 mutations.
Asunto(s)
Estrés Oxidativo , Enfermedad de Parkinson/fisiopatología , Eliminación de Secuencia , Ubiquitina-Proteína Ligasas/genética , Adulto , Estudios de Casos y Controles , Femenino , Glutatión Peroxidasa/sangre , Humanos , India , Peroxidación de Lípido , Masculino , Persona de Mediana Edad , Óxido Nítrico/sangre , Enfermedad de Parkinson/sangre , Estadísticas no Paramétricas , Superóxido Dismutasa/sangreRESUMEN
BACKGROUND: Parkinson's disease (PD) is a complex neurological disorder without any well-documented genotype-demography associations among sporadic variants. We recently reported PARK2 mutations to be constituting 40% of PD in this region and thus analysed how demographic variables associate with PARK2 mutations in 70 of these patients. METHODS: PD samples were screened by PCR single-strand conformation polymorphism (SSCP) and sequencing and their demographic data collected. Demographic and religion data was obtained from 1,010 randomly selected individuals of 120,000 patients visiting the Neurology Clinic and was compared with state database and PD patients. RESULTS: Sikhs from a rural background exhibited the majority of PARK2 mutations. The frequency of PARK2 mutations among females was significantly higher as compared to males (p < 0.015). The age of onset of PD patients with a rural background was found to be significantly lower as compared to patients with an urban background (p < 0.004). The demographic spectrum of the 1,010 randomly selected patients and the background population was found to be comparable. CONCLUSIONS: As PD patients with PARK2 mutations were found to be of sporadic origin and never-smokers, a non-redundant inverse relationship between founder PARK2 mutations and smoking is implicated to account for its high frequency. The predisposition of Sikhs to PARK2 mutations necessitates a larger study among its familial variants and a control smoker PD population. The spectrum of PARK2 mutations among Sikh smokers is difficult to study because of the religion-based aversion to smoking.
Asunto(s)
Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Ubiquitina-Proteína Ligasas/genética , Edad de Inicio , Anciano , ADN/genética , Exones/genética , Femenino , Eliminación de Gen , Humanos , India/epidemiología , Estilo de Vida , Masculino , Persona de Mediana Edad , Mutación/genética , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , Religión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Población Rural , Fumar/epidemiología , Factores Socioeconómicos , Bancos de Tejidos , Población UrbanaRESUMEN
BACKGROUND: Among several aetiological factors, PARK2 mutations are the most common cause of Parkinson disease (PD) that result in degeneration of dopaminergic neurons in the substantia nigra. METHODS: In order to examine the contribution of PARK2 mutations and corresponding Parkin expression in blood of North West Indian PD patients, the authors screened 120,000 patients from 2001 to 2006 for features of PD using UK Parkinson disease society brain bank clinical diagnostic criteria (UKPDBBC), and tested PARK2 mutations in 69 of those that fulfilled this criteria. 43 controls lacking extrapyramidal signs were also analysed. RESULTS: The PCR analysis revealed the occurrence of homozygous deletions in 28 of 69 samples analysed (40.5%) represented by exon-1 (15.9%), exon-3 (11.5%), and exon-12 (11.5%). Sequencing revealed point mutations in exon 4 and exon 9 in six of these patients (8.7%) including one novel missense Gly1083Trp mutation in one patient. Parkin estimation was done by combination of immunolocalisation and FACS analysis revealing reduced Parkin expression among PD patients. The mutations in exons 1, 3 and 12 among sporadic PD patients were found to be higher among younger onset variants (age<45 years). This report also constitutes the first evidence that PARK 2 mutations contribute to the aberration in Parkin expression in blood leading to PD.
Asunto(s)
Pruebas Genéticas/métodos , Trastornos Parkinsonianos/epidemiología , Trastornos Parkinsonianos/genética , Mutación Puntual/genética , Ubiquitina-Proteína Ligasas/genética , Áreas de Influencia de Salud , Cartilla de ADN/genética , Dopamina/metabolismo , Exones/genética , Femenino , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/patología , Reacción en Cadena de la Polimerasa , Prevalencia , Factores de Riesgo , Sustancia Negra/metabolismoRESUMEN
A case of a 35-year old female with a history of proximal weakness in lower limbs and bulkiness of both calves manifesting before ten years of age was reported. Clinical findings were suggestive of muscular dystrophy. Genetic analysis using polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP) and direct sequencing revealed several point mutations, which account for dystrophin dysfunction and DMD type pathogenesis.