Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.

Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.

[Evaluation of a program of application of the botulinum toxin type A in children with cerebral palsy in Vale do Jequitinhonha]. / Avaliação de um programa de aplicação de toxina botulínica tipo A em crianças do Vale do Jequitinhonha com paralisia cerebral.

The scope of this study was to evaluate the effects of a public program of application of botulinum toxin type A (BoNT-A) in terms of muscle spasticity, range of motion, quality of gait, functional independence and quality of life of children and adolescents with cerebral palsy (CP). A quasi-experimental study was conducted with 14 children with CP to evaluate the effects of three applications of BoNT-A, at intervals of three months. Children were assessed using the Modified Ashworth Rating Scale, the Manual Goniometer, the Physician Rating Scale, the Pediatric Evaluation of Disability Inventory (PEDI) and the Caregiver Questionnaire (CQ). There was a reduction of spasticity, an increase in the range of motion, an improvement of the functional abilities of self-care and mobility of PEDI and the areas of personal care, comfort and interaction/communication with the CQ. The BoNT-A application program for children and adolescents with CP, conducted in a public rehabilitation service in the Jequitinhonha Valley, was effective for the targeted population.

Avaliação de um programa de aplicação de toxina botulínica tipo A em crianças do Vale do Jequitinhonha com paralisia cerebral / Evaluation of a program of application of the botulinum toxin type A in children with cerebral palsy in Vale do Jequitinhonha

O objetivo do estudo foi avaliar os efeitos de um programa público de aplicação de toxina botulínica tipo A (TBA) na espasticidade muscular, amplitude de movimento, qualidade da marcha, independência funcional e qualidade de vida de crianças e adolescentes com paralisia cerebral (PC). Foi realizado um estudo quase experimental que avaliou os efeitos do emprego da TBA, aplicada três vezes, com intervalos de três meses, em 14 crianças com PC. Estas foram avaliadas através da Escala Modificada de Ashworth, Goniometria Manual, Physician Rating Scale, Inventário de Avaliação Pediátrica de Incapacidade (PEDI) e Questionário do Cuidador da Criança (QCC). Foi observada redução da espasticidade, aumento da amplitude de movimento, melhora das habilidades funcionais de autocuidado e mobilidade do PEDI e das áreas de cuidado pessoal, conforto e interação/comunicação do QCC. O programa de aplicação de TBA em crianças e adolescentes com PC, realizado em um núcleo de reabilitação público do Vale do Jequitinhonha, foi efetivo para a população beneficiada.

The scope of this study was to evaluate the effects of a public program of application of botulinum toxin type A (BoNT-A) in terms of muscle spasticity, range of motion, quality of gait, functional independence and quality of life of children and adolescents with cerebral palsy (CP). A quasi-experimental study was conducted with 14 children with CP to evaluate the effects of three applications of BoNT-A, at intervals of three months. Children were assessed using the Modified Ashworth Rating Scale, the Manual Goniometer, the Physician Rating Scale, the Pediatric Evaluation of Disability Inventory (PEDI) and the Caregiver Questionnaire (CQ). There was a reduction of spasticity, an increase in the range of motion, an improvement of the functional abilities of self-care and mobility of PEDI and the areas of personal care, comfort and interaction/communication with the CQ. The BoNT-A application program for children and adolescents with CP, conducted in a public rehabilitation service in the Jequitinhonha Valley, was effective for the targeted population.