RESUMO
Hypomorphic mutations in the gene encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme, ALPL in human or Akp2 in mice, cause hypophosphatasia (HPP), an inherited metabolic bone disease also characterized by spontaneous seizures. Initially, these seizures were attributed to the impairment of GABAergic neurotransmission caused by altered vitamin B6 (vit-B6) metabolism. However, clinical cases in human newborns and adults whose convulsions are refractory to pro-GABAergic drugs but controlled by the vit-B6 administration, suggest that other factors are involved. Here, to evaluate whether neurodevelopmental alterations are underlying the seizures associated to HPP, we performed morphological and functional characterization of postnatal homozygous TNAP null mice, a model of HPP. These analyses revealed that TNAP deficient mice present an increased proliferation of neural precursors, an altered neuronal morphology, and an augmented neuronal activity. We found that these alterations were associated with a partial downregulation of the purinergic P2X7 receptor (P2X7R). Even though deficient P2X7R mice present similar neurodevelopmental alterations, they do not develop neonatal seizures. Accordingly, we found that the additional blockage of P2X7R prevent convulsions and extend the lifespan of mice lacking TNAP. In agreement with these findings, we also found that exogenous administration of ATP or TNAP antagonists induced seizures in adult wild-type mice by activating P2X7R. Finally, our results also indicate that the anticonvulsive effects attributed to vit-B6 may be due to its capacity to block P2X7R. Altogether, these findings suggest that the purinergic signalling regulates the neurodevelopmental alteration and the neonatal seizures associated to HPP.
Assuntos
Fosfatase Alcalina/genética , Doenças Ósseas Metabólicas/genética , Hipofosfatasia/genética , Receptores Purinérgicos P2X7/genética , Convulsões/genética , Trifosfato de Adenosina/administração & dosagem , Fosfatase Alcalina/antagonistas & inibidores , Animais , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/fisiopatologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/fisiopatologia , Cálcio/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/metabolismo , Hipofosfatasia/fisiopatologia , Camundongos , Camundongos Knockout , Mutação , Receptores Purinérgicos P2X7/biossíntese , Convulsões/metabolismo , Convulsões/fisiopatologia , Vitamina B 6/administração & dosagemRESUMO
Ozone-therapy is used in humans as a coadjutant treatment in intervertebral disc diseases due to its analgesic, anti-inflammatory and antioxidant effects. References in dogs are scarce and limited to clinical cases (intradiscal/paravertebral infiltrations). The aim of this study was to assess the use of medical ozone (MO) as an adjunctive treatment in dogs with intervertebral disc protrusions (Hansen Type II/Chronic). A retrospective study was conducted in dogs diagnosed with intervertebral disc protrusions by MRI/CT in which MO was used as an adjuvant therapy to conventional medical treatment. Neurological examination and quality of life (QL) at the beginning and end of study were recorded, as well as posology and possible side effects. A total of 21 patients of different breeds and sex with a mean age of 12 years were included in this study. Results showed pain relief (7 ± 3 days) and improvement of neurologic signs (11 ± 9 days) with a consequent increasement in QL (13 ± 9 days). Thirteen out of the twenty-one patients (62%) showed a complete remission of the clinical signs. No serious adverse effects were observed. Medical ozone could be a potential complementary therapy to medical treatment in dogs with intervertebral disc protrusions. Prospective studies are necessary.
RESUMO
The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1-2 h and suggested progressive accumulation after the multiple dose treatment.
Assuntos
Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Canabidiol/administração & dosagem , Canabidiol/farmacocinética , Dronabinol/administração & dosagem , Dronabinol/farmacocinética , Administração Sublingual , Analgésicos/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Canabidiol/sangue , Doenças do Cão , Cães , Dronabinol/sangue , Combinação de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Sprays Orais , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Taxa Respiratória/efeitos dos fármacosRESUMO
Targeting of the CB2 receptor results in neuroprotection in the SOD1G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors are facilitated by their upregulation in the spinal cord of the mutant mice. Here, we investigated whether similar CB2 receptor upregulation, as well as parallel changes in other endocannabinoid elements, is evident in the spinal cord of dogs with degenerative myelopathy (DM), caused by mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in expression of the CB1 receptor (confirmed with CB1 receptor immunostaining) or NAPE-PLD, DAGL, FAAH and MAGL enzymes. In contrast, CB2 receptor levels were significantly elevated in DM-affected dogs determined by qPCR and western blotting, which was confirmed in the grey matter using CB2 receptor immunostaining. Using double-labelling immunofluorescence, CB2 receptor immunolabelling colocalized with GFAP but not Iba-1, indicating upregulation of CB2 receptors on astrocytes in DM-affected dogs. Our results demonstrate a marked upregulation of CB2 receptors in the spinal cord in canine DM, which is concentrated in activated astrocytes. Such receptors could be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Astrócitos/metabolismo , Modelos Animais de Doenças , Receptor CB2 de Canabinoide/metabolismo , Regulação para Cima , Esclerose Lateral Amiotrófica/enzimologia , Animais , CãesRESUMO
Introducción: actualmente existe un gran número de niños con retardo del neurodesarrollo, lo que constituye un significativo problema de salud de repercusión social. Objetivo: describir las características biopsicosociales que presentan los niños menores de 5 años con trastornos en el neurodesarrollo. Material y Métodos: se realizó un estudio observacional, descriptivo de corte transversal en el Policlínico Reina, Municipio Centro Habana, entre marzo de 2011 y febrero de 2012. El universo fue de 62 infantes que cumplieron con los criterios de inclusión y exclusión y sus padres dieron el. Para la recogida de la información se utilizaron las historias clínicas de los niños con retardo en el neurodesarrollo evaluados por el Programa de Atención temprana de la Habana Vieja, y se les aplicó a los padres una encuesta que incluyó variables biopsicosociales. Resultados: se evidenció que el antecedente prenatal de mayor relevancia fue la hipertensión arterial materna (22,58 %) y la asfixia intraparto (29,03 %) como antecedente natal más frecuente. Fue notable la presencia de trastornos del lenguaje en 16.12% de los pacientes. Resultó el área mental la más afectada (56.45%); no obstante, el área motora presentó dificultades en 43.56%. Conclusiones: predominaron en el estudio las madres de 18 a 35 años, amas de casa, con nivel de escolaridad alto y convivencia en pareja; con nivel económico y condiciones de la vivienda no adecuados. Prevalecieron los hábitos tóxicos en los padres y la conducta emocional de estos fue la aceptación. El afrontamiento de los padres al retardo del neurodesarrollo fue positivo.
Introduction: there are currently a large number of children with neurodevelopmental delay, which is a significant health problem for social impact. Objective: to describe the biopsychosocial characteristics presented by children under 5 years with neurodevelopmental disorders. Material and Methods: an observational, cross-sectional descriptive study was conducted in Reina Policlinic, Centro Habana municipality, between March 2011 and February 2012. We had the informed consent of the parents for the inclusion of 62 infants in the universe according to the inclusion and exclusion criteria. We used the medical records of children with neurodevelopmental delay assessed by the Early Care Program of Habana Vieja and was applied to a survey that included parents biopsychosocial variables. Results: it was evidenced that the most important prenatal antecedent was maternal hypertension (22.58%) and intrapartum asphyxia (29.03%) as the most common natal antecedent. Notable was the presence of language disorders in 16.12% of patients. The mental area turned out to be the most affected (56.45%); however, the motor area presented difficulties in 43.56%. Conclusions: mothers between 18 and 35 years predominated in the study, housewives with high educational level and living with a partner, with economic and unsuitable housing conditions. Toxic habits prevailed in parents and their emotional behavior was acceptance. The parents' coping with neurodevelopmental delay was positive.
RESUMO
Objetivo: evaluar un programa dirigido a los niños con retardo del neurodesarrollo. Métodos: estudio retrospectivo analítico de casos y controles, de la consulta de neurodesarrollo de La Habana Vieja. El universo y muestra estuvo constituido por 170 pacientes con retardo del neurodesarrollo entre los años 2000 y 2006. Se seleccionó aleatoriamente un grupo estudio constituido por 52 niños bajo peso con retraso del desarrollo sicomotor, y un grupo control formado por 118 niños normopesos con retraso del desarrollo sicomotor. Fueron evaluados por un equipo interdisciplinario, y se les realizó seguimiento trimestral, aplicándoles estimulación integral, fisiátrica, sicomotora, logopédica y en el hogar. Se aplicaron programas de estimulación como Isidoro Candell, Bobath y Vojta. Resultados: el grupo estudio presentó el menor por ciento de nivel escolar medio superior (42,31 por ciento) y el mayor por ciento de lactancia materna no exclusiva (20,08 por ciento). Además, presentó hipertonía (10,91 por ciento), trastornos de conducta (10,91 por ciento) y epilepsia-Down (3,64 por ciento). La evaluación motora presentó en el grupo estudio en la categoría normal, un ascenso a un 59 por ciento. El grupo estudio presentó el mayor por ciento de evolución agravada (12 por ciento) y el grupo control presentó un mayor por ciento de evolución favorable (39 por ciento). Conclusiones: la esfera motora presentó una respuesta más positiva que la esfera mental, y la evolución agravada se relacionó con los niños bajo peso con retardo del desarrollo sicomotor, aunque en general la evolución de los niños estimulados en nuestro programa presentó tendencia a la evolución favorable y superada.
Objective: to evaluate a program directed to children with neurodevelopment retardation. Methods: a retrospective analytical case-control study was conducted at the neurodevelopment department of Old Havana. The universe and the sample were composed of 170 patients with neurodevelopment retardation from 2000 to 2006. A study group that was made up of 52 low weight children with retardation of the psychomotor development, and a control group that consisted of 118 normoweight children with retardation of the psychomotor development were selected at random. They were evaluated by an interdisciplinary team and they had a quarterly follow-up. They were applied integral, physiatric, psychomotor, logopedic and home stimulation. Stimulation programs such as Isidoro Candell, Bobath and Vojta were used. RESULTS: the study group presented the lowest percent of middle educational level (42.31 percent) and the highest percent of non-exclusive breastfeeding (20.08 percent). It also had hypertony (10.91 percent), behavior disorders (10.91 percent) and epilepsy-Down syndrome (3.64 percent). In the study group, the motor evaluation in the normal category increased to 59 percent. The study group showed the highest percent of aggravated evolution (12 percentr), whereas the control group presented a higher percent of favorable evolution (39 percent). Conclusions: the motor sphere had a more positive response than the mental sphere, and the aggravated evolution was related to low weight children with psychomotor retardation, though in general the evolution of the children stimulated in our program had a trend towards a favorable and improved evolution.
Assuntos
Humanos , Criança , Desenvolvimento Infantil , Deficiências do DesenvolvimentoRESUMO
Evaluar un Proyecto Comunitario de Estimulación Temprana; describir los factores de riesgo biopsicosociales asociados al neurodesarrollo; relacionar la evolución con factores de riesgo y conocer la evolución de los pacientes en el proyecto . Se hace un estudio analítico (antes y después), cuyo universo estuvo constituido por 376 pacientes, con antecedentes de riesgo biosicosocial y/o con alguna manifestación de retardo del neurodesarrollo remitidos a consulta en el período comprendido entre 2000 y 2006, en el municipio Habana Vieja. Estos fueron evaluados por un equipo interdisciplinario, con un seguimiento trimestral a los que presentaron alteraciones del neurodesarrollo y aplicándoles estimulación semanal en el gimnasio. Se realizó cortes evaluativos a los niños de riesgo con examen clínico-neurológico y exámenes paraclínicos a los niños de riesgo. Para evaluar la efectividad de la intervención, se aplicaron los instrumentos de evaluación al inicio (3 meses) y al final (4 años); y se analizó la significación de las diferencias de los saltos cualitativos negativos o positivos en la escala motora y mental. Como resultado se tuvo que fue el insulto perinatal hipoxia el factor de riesgo más representado (52.72 por ciento) . Fue significativa la estimulación en hogar. La evolución favorable correspondió con el bajo peso mayor de 1 500gr, el mayor tiempo de permanencia en el programa (64.29por ciento) , los normopesos (61 por ciento) y la lactancia materna exclusiva. El mayor tiempo de evolución se relacionó con la categoría de evolución favorable (64.29 por ciento) . La evolución fue favorable en 53 por ciento y superada en 16por ciento. El resultado del proyecto se evaluó como satisfactorio
To evaluate a Project of Comunitary early neural stimulation, to describe the biosocial risks associated to the neural development and to evaluate the evolution of the risk factors as well to know the evolution of all the patients in the project were the aims of this work. An analytical (before and after) study was done, which universe was constituted by 376 patients with risk biosocial antecedents and or any manifestation of neural retardation , submitted to consultation in the period 2000 to 2006, in the Old Havana municipality . They were evaluated by multidisciplinary equipment, with a three-month follow up to those who presented alterations in the neural development , applying to them, early stimulation in the gymnasium. Evaluative exams were done to those kids at risk in the exams. To evaluate the activity of intervention, the instruments of intervention were applied at the beginning ( 3 months0 and at the end ( 4 years) , and we analyzed the significative differences in the qualitative and quantitative leaps in the motor or mental scale. As a result we obtained that hypoxia was the prenatal insult more represented. The favorable response corresponded with the low birth weight of 1500 gr, the more staying in the program (64, 29 percent), and the normal weight children (61 percent)and exclusive breast feeding. The Major time of evolution was related with the favorable cateory of evolution (64,29). The evolution was favorable in 53 percent and superated in 16 percent
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Criança , Deficiência Intelectual , Atenção Primária à Saúde , Planos e Programas de Saúde/tendências , Fatores de RiscoRESUMO
En el embarazo los hábitos tóxicos, como el fumar y la ingestión de bebidas alcohólicas, incrementan la producción de especies reactivas del oxígeno que pueden influir en la aparición y el desarrollo de hipertensión arterial y diabetes mellitus gestacional. La situación nutricional de la madre es decisiva en el estado vitamínico del recién nacido y las cantidades deficientes de vitaminas E y C en suero pueden incidir en una respuesta insuficiente al estrés oxidativo que representan el parto y en la recuperación posterior del niño. Fue objetivo de este trabajo establecer el efecto de diferentes factores sobre los niveles de las vitaminas E y C en suero de las embarazadas, y determinar cómo afectan al recién nacido. Se diseñó un estudio transversal de 203 casos durante un año de estudio. Se realizó una encuesta epidemiológica donde se evaluaron indicadores nutricionales, frecuencia de anemia referida, hábito de fumar, ingestión de bebidas alcohólicas, hipertensión arterial, diabetes mellitus, condiciones patológicas desarrolladas en el embarazo, problemas presentados durante el parto, peso al nacer y alteraciones en la evolución del recién nacido. Se preparó una variable en la cual se dividieron las concentraciones de a tocoferol y ácido ascórbico del recién nacido entre los valores de su madre y se evaluaron los niveles medios de las vitaminas E y C en el niño atendiendo a los niveles que presentaba la madre. Se utilizó el riesgo relativo (RR) y un intervalo de confianza (IC) del 95(por ciento)como medidas de asociación de los factores estudiados y las deficiencias de vitaminas E y C. Para evaluar el efecto de los factores que pudieran influir en la concentración de vitamina E en el recién nacido se ajustó una ecuación de regresión lineal. No se encontraron asociaciones que resultaran significativas entre los factores registrados con las deficiencias de vitaminas antioxidantes. Solo se encontró asociación débilmente significativa con las afectaciones en el desarrollo normal del embarazo y las concentraciones deficientes de vitamina C en la embarazada. El análisis del cociente obtenido al dividir las concentraciones de a tocoferol y ácido ascórbico del recién nacido entre los valores de concentración de su madre mostró que la mayor parte de los casos se clasificaban de acuerdo con los valores esperados y la variación del cociente estaba determinada por los valores de las concentraciones de la madre
Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Antioxidantes , Deficiência de Ácido Ascórbico , Inquéritos Epidemiológicos , Saúde Materno-Infantil , Deficiência de Vitamina ERESUMO
Se hace un estudio de 1 483 recién nacidos seguidos hasta el año de edad. Se analizan factores relacionados con el nacimiento del niño, la edad y la ocupación de la madre. Estos factores se corresponden con el tipo de alimentación que recibió cada niño en la maternidad y la duración de ésta. El 87 % de los niños egresó del Hospital con lactancia materna como único alimento, pero a los 2 meses de edad sólo el 9,5 % de éstos mantenían esta lactancia. El no inicio de la lactancia materna estuvo muy afectado por factores de riesgo relacionados con el nacimiento, pero el abandono de dicha lactancia se produjo en el mayor porcentaje de los niños, por referir la madre no tener suficiente leche para alimentar al bebé e implicar esto la prescripcióm facultativa de la indicación de otro tipo de leche o por decisión de la propia madre