Involvement of the Hsp70/TLR4/IL-6 and TNF-α pathways in delayed-onset muscle soreness.

Delayed-onset muscle soreness (DOMS) is a very common condition in athletes and individuals not accustomed to physical activity that occurs after moderate/high-intensity exercise sessions. The activation of microglial Toll-like receptor 4 (TLR4) in the spinal cord has been described to be important for the induction and maintenance of persistent pain. Based on that, we hypothesize that 70 kilodalton heat-shock protein (Hsp70), a mediator released by exercise, could activate microglial TLR4 in the spinal cord, releasing proinflammatory cytokines and contributing to the start of DOMS. In fact, we found that the knockout of TLR4, myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), or both tumor necrosis factor-α (TNF-α) receptor 1 and TNF-α receptor 2 in mice prevented the development of DOMS following acute aerobic exercise in contrast to the findings in male C57BL/6 wild-type mice. Furthermore, DOMS in exercised wild-type mice was also prevented after pre-treatment with microglia inhibitor, TLR4 antagonist, and anti-Hsp70 antibody. During exercise-induced DOMS, Hsp70 mRNA, TLR4 mRNA, and protein levels, as well as Iba-1 (a microglial marker), IL-6, and TNF-α protein levels, were increased in the muscle and/or spinal cord. Together, these findings suggest that Hsp70 released during exercise-induced DOMS activates the microglial TLR4/IL-6/TNF-α pathway in the spinal cord. Thus, the blockade of TLR4 activation may be a new strategy to prevent the development of DOMS before intense exercise.

Cannabidiol reduces lipopolysaccharide-induced nociception via endocannabinoid system activation.

Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious aetiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception. Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg. The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process. CBD treatment prevented LPS-induced nociception and TLR4 expression. AM630 reversed antinociception and reduced CBD-induced endocannabinoids up-regulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice. Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.

Preclinical evaluation of methotrexate-loaded polyelectrolyte complexes and thermosensitive hydrogels as treatment for rheumatoid arthritis.

This work proposes new methotrexate (MTX) loaded drug delivery systems (DDS) to treat rheumatoid arthritis via the intra-articular route: a poloxamer based thermosensitive hydrogel (MTX-HG), oligochitosan and hypromellose phthalate-based polyelectrolyte complexes (MTX-PEC) and their association (MTX-PEC-HG). MTX-PEC showed 470 ± 166 nm particle size, 0.298 ± 0.108 polydispersity index, +26 ± 2 mV and 74.3 ± 5.8% MTX efficiency entrapment and particle formation was confirmed by infrared spectroscopy and thermal analysis. MTX-HG and MTX-PEC-HG gelled at 36.7°C. MTX drug release profile was prolonged for MTX-HG and MTX-PEC-HG, and faster for MTX-PEC and free MTX. The in vivo effect of the MTX-DDSs systems was evaluated in induced arthritis rats as single intra-articular dose. The assessed parameters were the mechanical nociceptive threshold, the plasmatic IL-1ß level and histological analysis of the tibiofemoral joint. MTX-HG and MTX-PEC-HG performance were similar to free MTX and worse than oral MTX, used as positive control. All DDSs showed some irritative effect, for which further studies are required. MTX-PEC was the best treatment on recovering cartilage damage and decreasing allodynia. Thus, MTX-PEC demonstrated potential to treat rheumatoid arthritis, with the possibility of decreasing the systemic exposure to the drug.

Topographical curvature is sufficient to control epithelium elongation.

How biophysical cues can control tissue morphogenesis is a central question in biology and for the development of efficient tissue engineering strategies. Recent data suggest that specific topographies such as grooves and ridges can trigger anisotropic tissue growth. However, the specific contribution of biologically relevant topographical features such as cell-scale curvature is still unclear. Here we engineer a series of grooves and ridges model topographies exhibiting specific curvature at the ridge/groove junctions and monitored the growth of epithelial colonies on these surfaces. We observe a striking proportionality between the maximum convex curvature of the ridges and the elongation of the epithelium. This is accompanied by the anisotropic distribution of F-actin and nuclei with partial exclusion of both in convex regions as well as the curvature-dependent reorientation of pluricellular protrusions and mitotic spindles. This demonstrates that curvature itself is sufficient to trigger and modulate the oriented growth of epithelia through the formation of convex "topographical barriers" and establishes curvature as a powerful tuning parameter for tissue engineering and biomimetic biomaterial design.

Investigation of the Involvement of the Endocannabinoid System in TENS-Induced Antinociception.

Transcutaneous electrical nerve stimulation (TENS) promotes antinociception by activating the descending pain modulation pathway and consequently releasing endogenous analgesic substances. In addition, recent studies have shown that the endocannabinoid system controls pain. Thus, the present study investigated the involvement of the endocannabinoid system in TENS-induced antinociception of cancer pain using a cancer pain model induced by intraplantar (i.pl.) injections of Ehrlich tumor cells in male Swiss mice. Low- and high-frequency TENS was applied for 20 minutes to the mice's paws, and to investigate the involvement of the endocannabinoid system were used the N-(peperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pitazole-3-carboixamide (AM251), a cannabinoid CB1 receptor antagonist and (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenyl-methylester phosphonofluoridic acid (MAFP), an inhibitor of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase, injected by via i.pl., intrathecal (i.t.), and intradorsolateral periaqueductal gray matter (i.dl.PAG). Furthermore, liquid chromatography-tandem mass spectrometry, western blot, and immunofluorescence assays were used to evaluate the endocannabinoid anandamide levels, cannabinoid CB1 receptor protein levels, and cannabinoid CB1 receptor immunoreactivity, respectively. Low- and high-frequency TENS reduced the mechanical allodynia induced by Ehrlich tumor cells and this effect was reversed by AM251 and potentiated by MAFP at the peripheral and central levels. In addition, TENS increased the endocannabinoid anandamide levels and the cannabinoid CB1 receptor protein levels and immunoreactivity in the paw, spinal cord, and dorsolateral periaqueductal gray matter. These results suggest that low- and high-frequency TENS is effective in controlling cancer pain, and the endocannabinoid system is involved in this effect at both the peripheral and central levels. PERSPECTIVE: TENS is a nonpharmacological strategy that may be used to control cancer pain. Identification of a new mechanism involved in its analgesic effect could lead to the development of clinical studies as well as an increase in its application, lessening the need for pharmacological treatments.

Involvement of Spinal Cannabinoid CB2 Receptors in Exercise-Induced Antinociception.

Muscle pain affects approximately 11-24% of the global population. Several studies have shown that exercise is a non-pharmacological therapy to pain control. It has been suggested that the endocannabinoid system is involved in this antinociceptive effect. However, the participation of this pathway is unclear. The present study aimed to investigate whether spinal cannabinoid CB2 receptors participate in the exercise-induced antinociception. The inflammatory muscle pain model was induced by the intramuscular injection of carrageenan. Tactile allodynia and thermal hyperalgesia were determined with the von Frey filaments and hot-plate tests. C57BL/6J female mice underwent a swimming training protocol that lasted 3 weeks. This protocol of exercise reduced carrageenan-induced tactile allodynia and thermal hyperalgesia and this effect was prevented by the cannabinoid CB2 receptors inverse agonist AM630 and potentiated by MAFP (inhibitor of the enzyme that metabolizes endocannabinoids) and minocycline (microglia inhibitor). In addition, exercise increased the endocannabinoid anandamide levels and cannabinoid CB2 receptors expression whereas it reduced Iba1 (microglial marker) protein expression as well as pro-inflammatory cytokines (TNF-α and IL-1ß) in the spinal cord of mice with inflammatory muscle pain. Swimming training also reduced muscle temperature of carrageen-treated animals. The present study suggests that activation of spinal cannabinoid CB2 receptors and reduction of activated microglia are involved in exercise-induced antinociception.

Periferia, violência e estigma sob o enfoque da promoção da saúde: relato de experiência na comunidade de Mata Escura, Salvador/Bahia / Periphery, violence and stigma under the focus of health promotion: experience report in the community of Mata Escura, Salvador/Bahia / Periferia, violencia y estigma bajo el enfoque de la promoción de la salud: informe de experiencia en la comunidad de Mata Escura, Salvador/Bahia

Buscou-se neste estudo relatar a experiência de graduandos da área de saúde, com intervenções comunitárias, para enfrentamento do estigma e preconceito, resultantes do pertencimento a uma comunidade periférica permeada pela violência, em Mata Escura, Salvador/BA. As experiências partiram do componente curricular Programa de Integração Academia Serviço e Comunidade (PIASC), da Universidade do Estado da Bahia. As atividades ocorreram durante três semestres (2016-2017), abrangendo territorialização, diagnóstico situacional, planejamento estratégico situacional e intervenção comunitária. As intervenções foram desenvolvidas com jovens de uma escola estadual, com participação da Unidade Básica de Saúde e equipamentos sociais. Foram evidenciados aspectos históricos, sociais e lutas do bairro, além da problematização do contraste entre o estereótipo da comunidade e sua dinâmica cotidiana, raízes e potencialidades, com protagonismo dos moradores na construção das atividades. As experiências possibilitaram uma formação interdisciplinar, humanizada, crítica-reflexiva dos discentes. Para a comunidade de Mata Escura, estimularam a reflexão sobre a identidade social e de pertencimento.

It was sought to report the experience of undergraduate students in the health area, with community interventions, to face stigma and prejudice, resulting from belonging to a peripheral community permeated by violence, in Mata Escura, Salvador/BA. The experience started from the curricular component Teaching-Health Service-Community Integration Program (PIASC), of the State University of Bahia. It occurred during three semesters (2016-2017), including territorialization, situational diagnosis, situational strategic planning and community intervention. The interventions were developed with young people from a state school, with participation of the Basic Health Unit and social groups. Social aspects and struggles were highlighted, as well as the problematization of the contrast between the stereotype of the community and its daily dynamics, roots and potentialities, with the inhabitants' protagonism in the construction of activities. The experiences enabled the interdisciplinary, humanized, critical-reflective formation of the students. For the community, the activities stimulated reflection on social identity and belonging.

Se buscó reportar la experiencia de estudiantes universitarios del campo de la salud, con intervenciones comunitarias, para enfrentar el estigma y los prejuicios derivados de pertenecer a una comunidad periférica impregnada de violencia, en Mata Escura, Salvador/BA. Las experiencias partieron del componente curricular Programa de Integración Academia-Servicio-Comunidad (PIASC), de la Universidad del Estado de Bahía. Las actividades ocurrieron durante tres semestres (2016-2017), abarcando territorialización, diagnóstico situacional, planificación estratégica situacional e intervención comunitaria. Las intervenciones desarrollaron con jóvenes de una escuela estatal, participación de la Unidad Básica de Salud y equipamientos sociales. Se evidenciaron aspectos históricos, sociales y luchas del barrio, problematizando el contraste entre el estereotipo de la comunidad y su dinámica, raíces y potencialidades, con protagonismo de los habitantes en la construcción de las actividades. Las experiencias permitieron una formación interdisciplinaria, humanizada, crítica-reflexiva de los estudiantes. Para la comunidad, estimularon la reflexión sobre la identidad social y de pertenencia.

Indicadores de qualidade aplicados na assistência de enfermagem em cuidados paliativos: Revisão integrativa da literatura / Quality indicators applied in nursing care in palliative care: integrative literature review

Objetivo: Identificar na literatura indicadora de qualidade na assistência de enfermagem em cuidados paliativos. Método: Revisão integrativa da literatura em três bases de dados, com os descritores Nursing, palliative, indicator, palliative care, nurse care, quality indicator, cuidados paliativos, cuidado de enfermagem, tratamento paliativo, palliative assistence, indicadores de qualidade, hospice care, cuidados de conforto, atencíon de enfermería, health care, indicadores de calidad, com amostra final de 7 artigos. Resultados: Dentre os artigos encontrados foi evidenciado um foco no direcionamento dos indicadores para os cuidados multiprofissional, porém, a maioria dos indicadores encontrados se aplicavam aos cuidados de enfermagem e se dividiram nos aspectos físico, psicológico, social e espiritual. Conclusão: foi encontrada uma pequena quantidade de referências nas bases de dados em relação aos indicadores em cuidados paliativos necessitando de mais estudos voltados para essa área. (AU)

Objective: To identify in the literature quality indicators in nursing care in palliative care. Method: Integrative literature review in three databases with the keywords Nursing, palliative, indicator, palliative care, nurse care, quality indicator, palliative care, nursing care, palliative care, palliative assistance, quality indicators, hospice care, comfort care, nursing care, health care, quality indicators, with final sample of 7 articles. Results: Among the articles found there was a focus on the direction of indicators for multiprofessional care, however, most of the indicators found applied to nursing care and were divided into physical, psychological, social and spiritual aspects. Conclusion: A small number of references were found in the databases regarding the indicators in palliative care requiring further studies in this area. (AU)

Objetivo: identificar en la literatura indicadores de calidad en cuidados de enfermería en cuidados paliativos. Método: Revisión integral de la literatura en tres bases de datos con las palabras clave Enfermería, paliativos, indicadores, cuidados paliativos, cuidados de enfermería, indicadores de calidad, cuidados paliativos, cuidados de enfermería, cuidados paliativos, asistencia paliativa, indicadores de calidad, cuidados paliativos, atención de confort, atención de enfermería, atención de salud, indicadores de calidad, con muestra final de 7 artículos. Resultados: Entre los artículos encontrados se enfocó la dirección de los indicadores para la atención multiprofesional, sin embargo, la mayoría de los indicadores encontrados se aplicaron a la atención de enfermería y se dividieron en aspectos físicos, psicológicos, sociales y espirituales. Conclusión: se encontró un pequeño número de referencias en las bases de datos con respecto a los indicadores en cuidados paliativos que requieren más estudios en esta área. (AU)