RESUMEN
Interaction between the nervous and immune systems greatly contributes to inflammatory disease. In organs at the interface between our body and the environment, the sensory neuropeptide substance P (SP) is one key mediator of an acute local stress response through neurogenic inflammation but may also alter cytokine balance and dendritic cell (DC) function. Using a combined murine allergic inflammation/noise stress model with C57BL/6 mice, we show in this paper that SP--released during repeated stress exposure--has the capacity to markedly attenuate inflammation. In particular, repeated stress exposure prior to allergen sensitization increases DC-nerve fiber contacts, enhances DC migration and maturation, alters cytokine balance, and increases levels of IL-2 and T regulatory cell numbers in local lymph nodes and inflamed tissue in a neurokinin 1-SP-receptor (neurokinin-1 receptor)-dependent manner. Concordantly, allergic inflammation is significantly reduced after repeated stress exposure. We conclude that SP/repeated stress prior to immune activation acts protolerogenically and thereby beneficially in inflammation.
Asunto(s)
Alérgenos/administración & dosificación , Presentación de Antígeno/inmunología , Dermatitis Alérgica por Contacto/inmunología , Dermatitis Alérgica por Contacto/prevención & control , Mediadores de Inflamación/fisiología , Estrés Fisiológico/inmunología , Sustancia P/fisiología , Alérgenos/inmunología , Animales , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Dermatitis Alérgica por Contacto/patología , Modelos Animales de Enfermedad , Estimulación Eléctrica/efectos adversos , Femenino , Células de Langerhans/inmunología , Células de Langerhans/metabolismo , Células de Langerhans/patología , Ratones , Ratones Endogámicos C57BL , Ruido/efectos adversos , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Proyectos Piloto , Distribución AleatoriaRESUMEN
The aim of this study was to investigate autonomic cardiac control in patients with amyotrophic lateral sclerosis (ALS). Fifty-five patients with sporadic ALS (28 female and 27 male; average age 56.00 +/- 10.34 years) were compared to 30 healthy controls (17 female and 13 male; average age 42.87 +/- 11.91 years). Patients with previous history of cardiac disease, diabetes mellitus, and impaired respiratory function were excluded from the study. Cardiovascular autonomic tests according to Ewing, power spectrum analysis of RR variability (low- and high-frequency bands - LF and HF, LF/HF index), real-time beat-to-beat ECG signal monitoring with heart rate variability analysis and baroreflex function analysis were carried out in all patients. Time-domain parameters of heart rate variability (mean RR interval, SDNN, SDANN, SDNN index, rMSSD and pNN50%) were obtained from 24-h ECG monitoring. ALS patients had a significantly higher score of sympathetic (p <0.01) and parasympathetic (p <0.001) dysfunction, as well as of the overall score of autonomic dysfunction (p <0.001). LF/HF index was significantly increased; baroreflex sensitivity and time-domain parameters of heart rate variability were highly significantly decreased in ALS patients (p <0.001). Our results demonstrated impaired cardiac autonomic control in ALS with marked parasympathetic dysfunction and sympathetic predominance.
Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Enfermedades del Sistema Nervioso Autónomo/etiología , Cardiopatías/etiología , Adulto , Anciano , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Electrocardiografía/métodos , Femenino , Cardiopatías/diagnóstico , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Reflejo/fisiología , Análisis Espectral , Factores de TiempoRESUMEN
Airway reactivity is a phenomenon with vast clinical implications in children. The regulation of airway reactivity is influenced by local and central mechanisms. In airway diseases like bronchial asthma, the pathological regulation of the airway caliber causes symptoms like cough and dyspnea. Stress has long been considered a powerful manipulator in the physiological regulation of the airways. To explore potential mechanisms linking stress to the exacerbation of asthma, we developed an animal model that combines allergic airway inflammation and exposure to stress. This review summarizes the experimental data obtained in our and similar mouse models. First, we describe the innervation and neuromediators in the airways, next we analyze the occurrence of airway hyperresponsiveness, and then we explore the phenomenon of stress to finally connect all of the topics in a synopsis.
Asunto(s)
Asma/fisiopatología , Bronquios/fisiopatología , Broncoconstricción/inmunología , Sistema Respiratorio/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Asma/inmunología , Sistema Nervioso Autónomo/inmunología , Sistema Nervioso Autónomo/fisiopatología , Bronquios/inmunología , Bronquios/inervación , Modelos Animales de Enfermedad , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Mediadores de Inflamación/inmunología , Ratones , Neuroinmunomodulación/fisiología , Neumonía/inmunología , Neumonía/fisiopatología , Sistema Respiratorio/inmunología , Sistema Respiratorio/inervación , Estrés Psicológico/inmunologíaRESUMEN
The report presents a case of a 46-year-old male patient, previously treated because of dysphagia, pyrosis, vertigo while standing up and impotency. Manometric and pH-metric analysis showed presence of gastroesophageal reflux disease (GERD) caused by transient relaxation of lower esophageal sphincter (TRLES). Heart-rate variability showed decreased sympathetic function. Electromyoneurography showed a neurological lesion in muscles of upper extremities. The patient received midodrine and clonazepam which resolved this condition. These findings suggest that a neurological disorder can be a cause of GERD.
Asunto(s)
Reflujo Gastroesofágico/etiología , Insuficiencia Autonómica Pura/complicaciones , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To assess the frequency and type of peripheral neuropathy (PNP) in patients with myotonic dystrophy type 1 (DM1), as well as to identify factors that may be associated with this abnormality. METHODS: This study comprised 111 adult patients with DM1. Nerve conduction study was performed on sural, peroneal and median nerves of both limbs. RESULTS: PNP was somewhat more frequent in DM1 patients with glucose intolerance and diabetes mellitus (66.7 vs. 33.7%, P = 0.05). In DM1 patients with no glucose intolerance, diabetes mellitus and thyroid dysfunction, the most frequent type of PNP was demyelinating (70.0%) and motor (83.3%). PNP was more frequent in males (45.7 vs. 20.9%, P<0.05). Patients with PNP were older (43.7±7.3 vs. 39.6±9.6 years, P<0.05) and had a longer duration of DM1 compared to those without PNP (18.6±9.9 vs 12.7±8.3 years, P<0.01). DM1 patients with PNP had a higher body mass index) (24.9±5.5 vs. 22.4±4.2 kg/cm2, P<0.05), higher triglycerides (3.1±3.3 vs. 1.8±0.8 mmol/l, P<0.01), total cholesterol (6.2±1.4 vs. 5.4±1.1 mmol/l) and LDL cholesterol (4.3±1.2 vs. 3.4±1.0, P<0.05). Achilles reflexes were absent in 76.9% patients with PNP and in 51.9% patients without PNP (P<0.05). Patellar reflexes and muscle strength were similar in both groups (P>0.05). CONCLUSIONS: PNP was present in one-third of DM1 patients. The most common type was motor and demyelinating PNP. Our results suggest the association between the presence of peripheral nerve impairment in DM1 and male gender, age, duration of disease and certain metabolic parameters.
Asunto(s)
Distrofia Miotónica/complicaciones , Enfermedades del Sistema Nervioso Periférico/epidemiología , Enfermedades del Sistema Nervioso Periférico/etiología , Adulto , Electromiografía , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
The aim of this study was to analyze survival, causes of death and cardiologic predictors of sudden death in a large cohort of patients with myotonic dystrophy type 1 (DM1). The study was comprised of 171 adult DM1 patients hospitalized at the Neurology Clinic in a 20-year period. Severe electrocardiographic (ECG) abnormality included at least one of the following: rhythm other than sinus, PR interval of ≥240 ms, QRS complex duration of 120 ms or more, and second-degree or third-degree atrioventricular (AV) block. Survival data were analyzed by the Kaplan-Meier test, log-rank test and Cox regression analysis. During the mean follow-up period of 9.4±5.4 years, a pacemaker was implanted in 5.8% of DM1 patients and 14% of patients died. The mean age at death was 55.6±12.5 years. The most common causes of death in our cohort were sudden death (41.7%) and respiratory failure (29.2%). The presence of palpitations (hazard ratio [HR]=4.7, p<0.05) and increased systolic blood pressure (HR=9.8, p<0.05) were significant predictors of sudden death. Among ECG parameters, severe ECG abnormality (HR=4.7, p<0.05), right bundle branch block (RBBB; HR=3.9, p<0.05) and bifascicular block (HR=5.8, p<0.05) were significant predictors of sudden death.
Asunto(s)
Muerte Súbita Cardíaca/etiología , Distrofia Miotónica/complicaciones , Distrofia Miotónica/mortalidad , Adulto , Edad de Inicio , Causas de Muerte , Muerte Súbita Cardíaca/epidemiología , Electrocardiografía , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Modelos de Riesgos Proporcionales , Insuficiencia Respiratoria/epidemiología , Insuficiencia Respiratoria/etiología , Estudios RetrospectivosAsunto(s)
Atrofia Bulboespinal Ligada al X/complicaciones , Síndromes Miasténicos Congénitos/etiología , Anticuerpos/metabolismo , Atrofia Bulboespinal Ligada al X/genética , Electromiografía , Humanos , Masculino , Persona de Mediana Edad , Síndromes Miasténicos Congénitos/genética , Receptores Androgénicos/genética , Receptores Colinérgicos/inmunologíaRESUMEN
A neurogenic component in atopy and allergy is evident and potentially of great pathogenic relevance. Stress was recently shown to activate elements of this component and is vividly discussed as a cause of exacerbation. However, to date, scientific proof of stress-induced neuronal plasticity and neuro-immune interaction in atopy or allergy remains lacking. Here we show early evidence that exposure to sound stress and atopic dermatitis-like allergic dermatitis (AD) equipotently raise the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P (SP) in mice. Stress increases AD readout parameters by at least 30% (eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, epidermal thickness). This dramatic pathologic exacerbation is associated with increased neurogenic inflammation (degranulated mast cells; interstitial neuropeptidergic dense core granules, mast cell apoptosis, endothelial gaping). Key features of AD exacerbation could not be induced in mice lacking the neurokinin-1 SP receptor (NK1). Interestingly, stress had no significant additional effect on CD4+ cell number, but shifted the cytokine profile toward TH2 in skin. Thus, we conclude that stress primarily exacerbates AD via SP-dependent cutaneous neurogenic inflammation and subsequent local cytokine shifting and should be considered as a therapeutic target, while it offers a convincing pathogenic explanation to affected patients and their frustrated physicians alike.
Asunto(s)
Dermatitis Atópica/fisiopatología , Inflamación Neurogénica/fisiopatología , Estrés Psicológico/fisiopatología , Sustancia P/inmunología , Animales , Recuento de Linfocito CD4 , Citocinas/metabolismo , Dermatitis Atópica/inmunología , Femenino , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Fibras Nerviosas/metabolismo , Inflamación Neurogénica/inmunología , Receptores de Neuroquinina-1/genética , Receptores de Neuroquinina-1/metabolismo , Piel/inmunología , Piel/inervación , Estrés Psicológico/inmunología , Sustancia P/metabolismo , Células Th2/metabolismoRESUMEN
Myasthenia gravis (MG) is a heterogeneous disease composed of several entities with disturbed neuromuscular transmission. The most frequent and clinically most important form of MG is an acquired autoimmune MG which includes more than 90% of all patients with failure of neuromuscular transmission. The main clinical feature of MG is changeable pathologic fatigability and weakness of one or more skeletal muscles and variable distribution of affected muscles. The disease is characterized by relapses and remissions. In 15% of patients the symptoms are limited to extraocular muscles causing variable ptosis, squint and double vision (Ocular MG). In remaining 85% of patients, during the first three years, the disease involves the majority of the head, neck and extremity skeletal muscles (Generalized MG). The clinical diagnosis may be sufficiently established by typical history, present or induced neurological signs of changeable muscle weakness and positive pharmacological tests. The assessment of the severity of the disease as well as the assessment of working capability is performed according to the classification recommended by Myasthenia Gravis Foundation of America (MGFA). The standardized score of the disease severity is based on testing function and strength of 9 groups of skeletal muscles. At the onset of the disease, regardless of the clinical form, the patient is incapable of work and subjected to hospitalization, clinical investigation and treatment. The efficacy of anticholinesterase drugs, thymectomy and/or immunosuppression determines the working capability and is recommended to be assessed six months after the initiation of treatment procedure.
Asunto(s)
Miastenia Gravis/diagnóstico , Evaluación de Capacidad de Trabajo , Humanos , Miastenia Gravis/clasificación , Miastenia Gravis/terapiaRESUMEN
Recent findings indicate that nitric oxide (NO*) over-production might be an important factor in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). We measured significantly higher concentrations of uric acid and thiol group-containing molecules (R-SH groups) in the cerebrospinal fluid (CSF) from SALS patients compared to controls. The above factors, together with a slightly increased free iron concentration found in the CSF, favour conditions necessary for the formation of the dinitrosyl iron complex, capable of NO* bio-transformation. Thus, we performed ex vivo saturation of CSF (from both SALS patients and controls) with NO*. A decrease in the level of R-SH was found. This was more pronounced in the CSF from SALS patients. In the CSF from SALS patients the production of nitrite and hydroxylamine was greater than that observed in the CSF from controls. Moreover, we also found increased Cu,Zn-SOD activity in the CSF from SALS patients (when compared to control subjects) but no activity corresponding to Mn-SOD in any CSF samples. As Cu,Zn-SOD can react with nitroxyl forming NO*, the conditions for a closed, but continuous, loop of NO* biotransformation are present in the CSF of ALS patients.
Asunto(s)
Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Hierro/química , Óxido Nítrico/líquido cefalorraquídeo , Óxido Nítrico/farmacocinética , Óxidos de Nitrógeno/química , Adulto , Anciano , Femenino , Humanos , Hidroxilamina/metabolismo , Hierro/metabolismo , Masculino , Persona de Mediana Edad , Nitritos/metabolismo , Oxidación-Reducción , Superóxido Dismutasa/metabolismoRESUMEN
Microglial cells are the pathologic sensors in the brain. ATP released from damaged cells is a candidate for signalling neural injury to microglia. Moreover, ATP is an extracellular messenger for propagating astrocyte activity in the form of Ca2+ waves. To test for the functional expression of purinoreceptors in microglial cells we employed the patch-clamp technique in acute slices of adult mouse brain. ATP triggered a nonselective cationic and a K+ current. Pharmacological screening with purinergic ligands indicated the presence of P2Y1 and P2Y2/4 receptors linked to the activation of a K+ current and P2X receptors, including P2X7, linked to the activation of a nonselective cationic current. These findings suggest that microglial cells in situ express different purinergic receptors with distinct sensitivity and functional coupling. To test for the involvement of purinoreceptors in microglial activation, we stimulated cultured microglial cells with lipopolysaccharide and measured the release of tumour necrosis factor alpha, interleukin-6, interleukin-12 and macrophage inflammatory protein 1alpha, induction of K+ outward currents and nitric oxide release. All these parameters were reduced in the presence of purinergic ligands, indicating that purinergic receptor activation attenuated indicators of microglial activation.
Asunto(s)
Adenosina Trifosfato/análogos & derivados , Encéfalo/fisiología , Microglía/fisiología , Receptores Purinérgicos/fisiología , Adenosina Trifosfato/farmacología , Adenosina-5'-(N-etilcarboxamida)/farmacología , Animales , Animales Recién Nacidos , Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Canales de Cloruro/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Técnicas In Vitro , Lipopolisacáridos/farmacología , Magnesio/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Conducción Nerviosa/efectos de los fármacos , Óxido Nítrico/metabolismo , Técnicas de Placa-Clamp/métodos , Canales de Potasio/efectos de los fármacos , Receptores Purinérgicos/clasificación , Receptores Purinérgicos/genética , Factores de Tiempo , Uridina Difosfato/farmacología , Uridina Trifosfato/farmacología , Vasodilatadores/farmacologíaRESUMEN
gamma-Aminobutyric acid (GABA) can act as a neuroprotective agent besides its well-established role as the main inhibitory neurotransmitter in the CNS. Here we report that microglial cells express GABA(B) receptors indicating that these prominent immunocompetent cells in the brain are a target for GABA. Agonists of GABA(B) receptors triggered the induction of K(+) conductance in microglial cells from acute brain slices and in culture. Both subunits of GABA(B) receptors were identified in cultured microglia by Western blot analysis and immunocytochemistry, and were detected on a subpopulation of microglia in situ by immunohistochemistry. In response to facial nerve axotomy, we observed an increase in GABA(B) receptor expressing microglial cells in the facial nucleus. We activated microglial cells in culture with lipopolysaccharide (LPS) to induce the release of interleukin-6 and interleukin-12p40. This release activity was attenuated by simultaneous activation of the GABA(B) receptors indicating that GABA can modulate the microglial immune response.