Stimulation of the P2X7 receptor by ATP induces cell membrane depolarization, increase in intracellular Ca2+ concentration, and, in most cases, permeabilization of the cell membrane to molecules up to 900 Da. After the activation of P2X7, at least two phenomena occur: the opening of low-conductance (8 pS) cationic channels and pore formation. At least two conflicting hypotheses have been postulated to reconcile these findings: 1) the P2X7 pore is formed as a result of gradual permeability increase (dilation) of cationic channels, and 2) the P2X7 pore represents a distinct channel, possibly activated by a second messenger and not directly by extracellular nucleotides. In this study, we investigated whether second messengers are necessary to open the pore associated with the P2X7 receptor in cells that expressed the pore activity by using the patch-clamp technique in whole cell and cell-attached configurations in conjunction with fluorescent imaging. In peritoneal macrophages and 2BH4 cells, we detected permeabilization and single-channel currents in the cell-attached configuration when ATP was applied outside the membrane patch in a condition in which oxidized ATP and Lucifer yellow were maintained within the pipette. Our data support Ca2+ as a second messenger associated with pore formation because the permeabilization depended on the presence of intracellular Ca2+ and was blocked by BAPTA-AM. In addition, MAPK inhibitors (SB-203580 and PD-98059) blocked the permeabilization and single-channel currents in these cells. Together our data indicate that the P2X7 pore depends on second messengers such as Ca2+ and MAP kinases.

CONTEXT Research activity is not a mandatory component of medical education in many developing countries, including Brazil, although such experiences can have a positive impact on the quality of medical education. The interest and involvement of medical students in research and the barriers they face in accessing research training in developing countries have not been adequately addressed.OBJECTIVES We sought to assess the availability of scientific training programmes in Brazilian medical schools, the degree of involvement of medical students in these programmes, the main barriers to student involvement in research and possible reasons for the lack of scientific training programmes.METHODS This study examined 13 medical programmes conducted in six Brazilian states. A total of 1004 medical students were interviewed. We evaluated the availability of scientific training in the institutions attended by these students, the participation of the students in such activities and students' reasons for not joining such programmes based on student answers to our questionnaire.RESULTS Although only 7% of the medical students expressed no interest in research, only 60% of them were involved in research training. Students regarded a lack of institutional incentive as the most significant barrier to their participation in research activities. Other significant barriers included defective infrastructure and insufficient time available for professors to mentor undergraduate students. According to the feedback from the students, eight of the 13 schools investigated featured structured programmes for scientific training. However, a mean of only 47% of students participated in scientific training programmes on their campuses and 13% of students were compelled to pursue such activities off-campus.CONCLUSIONS Although scientific training during medical education in Brazil is still less frequent than expected, most of the students were interested in research activities. The barriers to undergraduate scientific training described in this paper may help the Brazilian government improve research training in medical schools. These issues might also be explored in other developing countries.

A educação médica passa por modificações na doutrina e na prática da formação profissional, conectada à contemporaneidade do mundo globalizado. No contexto do Sistema Único de Saúde (SUS), aumenta o interesse de diferentes sujeitos em relação ao ensino médico, devido aos aspectos políticos e comunitários e com repercussões nas mudanças nos serviços de saúde. Iniciativas de incentivo às mudanças curriculares em medicina são adotadas para incrementar melhorias na formação médica. Nesse contexto se insere o Projeto de Incentivo a Mudanças Curriculares para os Cursos de Medicina (Promed). Com o objetivo de analisar a percepção de alunos sobre mudanças curriculares na educação médica, pesquisamos seis cursos médicos, em três estados brasileiros, usando questionários e entrevistas. Alguns pressupostos das Diretrizes Curriculares Nacionais não foram incrementados, mas o desdobramento do Promed possibilitou um programa ampliado de incentivos a mudanças curriculares. Mesmo tendo caráter exploratório, este estudo aponta a necessidade de estudos prospectivos para conhecer os impactos dos incentivos às mudanças curriculares do ensino médico, sintonizando-o, assim, com as necessidades de saúde da população.

We were unable to demonstrate any significant benefit from amitriptyline plus fluoxetine over amitriptyline alone in the treatment of chronic daily headache/transformed migraine. Because of the small number of subjects involved and the short duration of our study, a type II error cannot be excluded.

Abstract:The P2X7 receptor (P2X7R) is a nonselective cation channel that is activated by extracellular ATP and triggers the secretion of several proinflammatory substances, such as IL-1β, IL-18, TNF-α, and nitric oxide. Recently, several preclinical studies have demonstrated that this receptor participates in inflammation and pain mechanisms. Taken together, these results indicate that P2X7R is a promising pharmacological target, and compounds that modulate the function of this receptor show potential as new anti-inflammatory medicines. In this review, we discuss aspects of P2X7R pharmacology and the participation of this protein in inflammation and pain and provide an overview of some promising compounds that have been tested as antagonists of P2X7R, with clinical applicability.