Luiz Anastacio Alves

Amitriptyline Versus Amitriptyline Combined With Fluoxetine in the Preventative Treatment of Transformed Migraine: A Double‐Blind Study

Background and Objectives.—Antidepressants are often used to treat chronic daily headache disorders such as transformed migraine, in part because of the high prevalence of associated mood disorder. We conducted this study to evaluate the efficacy and tolerability of combined treatment with amitriptyline and fluoxetine compared with amitriptyline alone for chronic daily headache due to transformed migraine.

Physiological Roles and Potential Therapeutic Applications of the P2X7 Receptor in Inflammation and Pain

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.

Hepatocyte xenotransplantation for treating liver disease

Bonavita AG, Quaresma K, Cotta‐de‐Almeida V, Alves Pinto M, Magalhães Saraiva R, Anastácio Alves L. Hepatocyte xenotransplantation for treating liver disease. Xenotransplantation 2010; 17: 181–187.

Student views of research training programmes in medical schools

Medical Education 2011:45: 748–755

Mudanças curriculares no ensino médico brasileiro: um debate crucial no contexto do Promed

Medical Education is undergoing modifications in the doctrine and in the practice of professional education as a consequence of todays globalized world. With respect to the Brazilian Health System, different subjects show increasing interest in medical education and in changes in the healthcare services. There are initiatives for encouraging changes in the medical curriculum for improving medical education. The Program for the Encouragement of Curricular Changes in Medical Courses (Promed) was implemented in this context. In order to analyze the opinion of students about changes in the curriculum of the medical course, we studied six medical schools in three Brazilian states, using questionnaires and interviews. Some of the propositions of the National Curriculum Guidelines have not been met but Promed gave rise to a new extensive program of changes in the medical curriculum. Even having exploratory character, this work clearly indicates the need for prospective studies in order to know the impact of Promed on medical education for adapting it to the healthcare needs of the population.

Gap junctions: a novel route for direct cell-cell communication in the immune system?

Abstract Functional gap junctions are found in thymus, bone marrow and lymph node microenvironments; formed by connexins, they allow the passage of small molecules between adjacent cells. Various experimental approaches have indicated the existence of heterocellular gap junctions between lymphocytes and microenvironmental cells in these organs. Here, Luiz Alves and colleagues discuss the suggestion that they represent an additional route for cell–cell communication in the immune system.

Flow cytometry analysis of gap junction‐mediated cell–cell communication: Advantages and pitfalls

Since the first morphological description of the gap junctions use electron microscopy, a considerable number of techniques has been introduced to evaluate gap junction channel functionality, many of which use dye transfer techniques, such as dye injection and fluorescent dye transfer, analyzed by flow cytometry.

Gap junction modulation by extracellular signaling molecules: the thymus model

Gap junctions are intercellular channels which connect adjacent cells and allow direct exchange of molecules of low molecular weight between them. Such a communication has been described as fundamental in many systems due to its importance in coordination, proliferation and differentiation. Recently, it has been shown that gap junctional intercellular communication (GJIC) can be modulated by several extracellular soluble factors such as classical hormones, neurotransmitters, interleukins, growth factors and some paracrine substances. Herein, we discuss some aspects of the general modulation of GJIC by extracellular messenger molecules and more particularly the regulation of such communication in the thymus gland. Additionally, we discuss recent data concerning the study of different neuropeptides and hormones in the modulation of GJIC in thymic epithelial cells. We also suggest that the thymus may be viewed as a model to study the modulation of gap junction communication by different extracellular messengers involved in non-classical circuits, since this organ is under bidirectional neuroimmunoendocrine control.

The P2X7 receptor: Shifting from a low- to a high-conductance channel — An enigmatic phenomenon?

The general structure of the P2X7 receptor (P2X7R) is similar to the structure of other P2X receptor family members, with the exception of its C terminus, which is the longest of this family. The P2X7R activates several intracellular signaling cascades, such as the calmodulin, mitogen-activated protein kinase and phospholipase D pathways. At low concentrations of ATP (micromolar range), P2X7R activation opens a cationic channel, similarly to other P2X receptors. However, in the presence of high concentrations of ATP (millimolar range), it opens a pathway that allows the passage of larger organic cations and anions. Here, we discuss both the structural characteristics of P2X7R related to its remarkable functions and the proposed mechanisms, including the dilation of the endogenous pore and the integration of another channel. In addition, we highlight the importance of P2X7R as a therapeutic target.

Pharmacological properties of a pore induced by raising intracellular Ca2

Recent studies on the P2X(7) receptor in 2BH4 cells and peritoneal macrophages have demonstrated that the raise in intracellular Ca(2+) concentration induces a pore opening similar to P2X(7) receptor pore. Herein, we have investigated whether the pore activated by the elevation of intracellular Ca(2+) concentration is associated to P2X(7) receptor. Using patch clamp in cell attached, whole cell configuration, and dye uptake, we measured the pore opening in cell types that express the P2X(7) receptor (2BH4 cells and peritoneal macrophages) and in cells that do not express this receptor (HEK-293 and IT45-RI cells). In 2BH4 cells, the stimulation with ionomycin (5-10 microM) increased intracellular free Ca(2+) concentration and induced pore formation with conductance of 421 +/- 14 pS, half-time (t(1/2)) for ethidium bromide uptake of 118 +/- 17 s, and t(1/2) for Lucifer yellow of 122 +/- 11 s. P2X(7) receptor antagonists did not block these effects. Stimulation of HEK-293 and IT45-RI cells resulted in pore formation with properties similar to those found for 2BH4 cells. Connexin hemichannel inhibitors (carbenoxolone and heptanol) also did not inhibit the pore-induced effect following the increase in intracellular Ca(2+) concentration. However, 5-(N,N-hexamethylene)-amiloride, a P2X(7) receptor pore blocker, inhibited the induced pore. Moreover, intracellular signaling modulators, such as calmodulin, phospholipase C, mitogen-activated protein kinase, and cytoskeleton components were important for the pore formation. Additionally, we confirmed the results obtained for electrophysiology by using the flow cytometry, and we discarded the possibility of cellular death induced by raising intracellular Ca(2+) at the doses used by using lactate dehydrogenase release assay. In conclusion, increased concentration in intracellular Ca(+2) induces a novel membrane pore pharmacologically different from the P2X(7) associated pore and hemigap-junction pore.