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Clinical Research Networks (CRNs) are means to improve healthcare delivery, quality of care and patient outcomes. The Oswaldo Cruz Foundation (Fiocruz), Latin America's leading health research organization, has established a CRN to promote interaction and collaboration among its clinical research experts. After a decade of operation, a revitalization process was undertaken out of the need to improve its functionality. This study aimed to describe the evaluation process of the Fiocruz Clinical Research Network (RFPC) by gathering the opinions and perspectives of its members and identifying the network structure. The goal was to improve scientific collaboration and member engagement, thereby increasing the integration, effectiveness, and impact of clinical research conducted at the institution. Clinical research professionals at Fiocruz were invited to participate in an online questionnaire to collect information about their professional experience, the benefits and constraints of participating in research networks, relevant discussion topics, and the challenges of complying with Good Clinical Practices (GCP). With the help of social network analysis, a deeper understanding of the dynamics and structure of professional communication networks was obtained. The questionnaire was completed by 122 professionals (response rate 50.4%), with most respondents being principal investigators (PIs) with more than 10 years of professional experience (24.6%). Participation in research networks was considered beneficial, particularly in working groups (48.4%), and as an opportunity to exchange experiences with other professionals (44.3%). Almost half of the participants (48.4%) did not identify any barriers to participating in a network. Topics that required further discussion included data management, biorepositories and biobanks, and ethical and regulatory issues. Challenges to conducting clinical research with GCP standards included strategic support and funding, staffing and training, data management, infrastructure, quality management, and collaboration. Communication within the research network was loosely structured, with the most experienced professionals holding central positions. This analysis provided valuable insights to support the management of the RFPC. It highlighted the internal community's interests and expectations, identified key areas for improvement in GCP implementation, and influential professionals who could improve information sharing and national integration. The findings have far-reaching implications that can be applied in different contexts. They contribute to the ongoing discussion on the establishment and management of research networks., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lopes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Difficult access to birth care services is associated with infant and neonatal mortality and maternal morbidity and mortality. In this study, data from the Brazilian Unified National Health System (SUS) were used to map the evolution of geographic accessibility to hospital birth of usual risk in the state of Rio de Janeiro, Brazil, corresponding to 418,243 admissions in 2010-2011 and 2018-2019. Travel flows, distances traveled, and intermunicipal travel time between the pregnant women's municipality and hospital location were estimated. An increase from 15.9% to 21.5% was observed in the number of pregnant women who needed to travel. The distance traveled increased from 24.6 to 26km, and the travel time from 76.4 to 96.1 minutes, with high variation between Health Regions (HR). Pregnant women living in HR Central-South traveled more frequently (37.4-48.9%), and those living in the HRs Baía da Ilha Grande and Northwest traveled the largest distances (90.9-132.1km) and took more time to get to the hospital in 2018-2019 (96-137 minutes). The identification of municipalities that received pregnant women from many other municipalities and municipalities that treated a higher number of pregnant women (hubs and attraction poles, respectively) reflected the unavailability and disparities in access to services. Regional inequalities and reduced accessibility highlight the need to adapt supply to demand and review the distribution of birth care services in the state of Rio de Janeiro. This study contributes to research and planning on access to maternal and child health services and can be used as a reference study for other states in the country.

Background: The Global Virome Project (GVP) was proposed in 2018 as an evolution of the USAID PREDICT project and was presented as a "collaborative scientific initiative to discover zoonotic viral threats and stop future pandemics". The immediate response was mixed, with public health and scientific communities representatives showing skepticism, if not direct opposition., Objectives: The economic, social, and health consequences of the coronavirus disease 2019 (COVID-19) pandemic demonstrated how unprepared the world was in the face of new pandemics. This paper analyses the impact of the GVP on the scientific and public health communities., Methods: Published scientific articles that cited the two 2018 seminal publications proposing the project were analysed using social network analysis methods., Findings: Encompassing the periods before and after the onset of the Covid-19 pandemic, the results indicate that (i) the concepts of the GVP have received more support than opposition in the scientific literature; (ii) its foundations should be updated to address the specific criticisms., Main Conclusions: Shifting focus to national virome projects can provide tangible, regional benefits that can positively contribute towards a consensus on achieving a high level of preparedness for the ever-present possibility of the following global viral pandemic.

The COVID-19 pandemic triggered unprecedented scientific efforts worldwide and launched several initiatives to promote international cooperation. Because international scientific collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) are not always balanced, analyzing research leadership helps to understand the global dynamics of knowledge production during COVID-19. In this study, we focused on HIC-LMIC collaborations on COVID-19 research in 469,937 scientific publications during the first 2 years of the pandemic (2020-2021). Co-authorship and authors' affiliation were used to identify international collaborations, according to country income level. The leadership analysis considered the countries of the first and last authors of publications. The results show that (i) most publications with international collaborations (49.3%) involved researchers from HICs and LMICs; (ii) collaborative research between HICs and LMICs addressed relevant public health needs; (iii) HIC-LMIC collaborations were primarily led by researchers from the United States, China, the United Kingdom, and India; (iv) most HIC-LMIC publications (44%) had shared leadership, with research interests linked to national expertise and global interests. This study contributes to the analysis of research collaborations on COVID-19 and sheds light on North-South relations in the production and dissemination of scientific knowledge., Competing Interests: Competing interestsThe authors have no competing interests to declare., (© The Author(s) 2023.)

The advancement of drug repurposing (DR) relies on scientific leadership and innovative institutions with access to knowledge. We performed a bibliometric and social network analysis (covering the period 2011-2020) to map the DR research trends and to identify innovation and knowledge leaders (IKLs). The indexing rate of DR publications has steadily increased. Major research areas included emerging viruses, cancer, methodological approaches, preclinical research, and infectious diseases. Government and academia accounted for nearly 65% of funding. Using a combination of network centrality metrics, 41 IKLs affiliated to central and pericentral institutions in the global research network were identified. These IKLs can facilitate the flow of knowledge and are best positioned to promote interactions within the network, with the potential to contribute significantly to advancing the DR field., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Geographic accessibility to healthcare services is a fundamental component in achieving universal health coverage, the central commitment of the Brazilian Unified Health System (SUS). For cancer patients, poor accessibility has been associated with inadequate treatment, worse prognosis, and poorer quality of life., Methods: We explored nationwide healthcare data from the SUS health information systems, and mapped the geographic accessibility to cancer treatment in two time-frames: 2009-2010 and 2017-2018. We applied social network analysis (SNA) to estimate the commuting route, flow, and distances travelled by cancer patients to undergo surgical, radiotherapy, and chemotherapy treatment., Findings: A total of 12,751,728 treatment procedures were analyzed. Overall, more than half of the patients (49·2 to 60·7%) needed to travel beyond their municipality of residence for treatment, a fact that did not change over time. Marked regional differences were observed, as patients living in the northern and midwestern regions of the country had to travel longer distances (weighted average of 296 to 870 km). Cancer care hubs and attraction poles were mostly identified in the southeast and northeast regions, with Barretos being the main hub for all types of treatment throughout time., Interpretation: Important regional disparities in the accessibility to cancer treatment in Brazil were revealed, suggesting the need to review the distribution of specialized care in the country. The data presented here contribute to ongoing research on improving access to cancer care and can provide reference to other countries, offering relevant data for oncological and healthcare service evaluation, monitoring, and strategic planning., Funding: This work was funded by the Oswaldo Cruz Foundation - Fiocruz (Inova - no. 8451635123 to BPF) and the National Council for Scientific and Technological Development - CNPq (no. 407060/2018-9 to BPF); Coordination for the Improvement of Higher Education Personnel - CAPES (scholarship to PCA, Finance Code 001); and Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN)., Resumo: A acessibilidade geográfica aos serviços de saúde é um componente fundamental para o alcance da cobertura universal de saúde, compromisso central do Sistema Único de Saúde (SUS). Para pacientes com câncer, a baixa acessibilidade aos serviços especializados tem sido associada ao tratamento inadequado, piora no prognóstico e na qualidade de vida.Neste estudo, dados de saúde dos sistemas de informação em saúde do SUS foram utilizados para mapear a acessibilidade geográfica ao tratamento do câncer em dois períodos: 2009-2010 e 2017-2018. Aplicamos a análise de redes sociais (ARS) para estimar os fluxos de deslocamento e as distâncias percorridas por pacientes com câncer para receberem tratamento cirúrgico, radioterápico e quimioterápico.Um total de 12.751.728 procedimentos de tratamento foram analisados. Em geral, mais da metade dos pacientes (49,2 a 60,7%) precisaram se deslocar de seus municípios de residência para receber tratamento, fato que não mudou comparando os dois períodos de tempo analisados. Foram observadas importantes diferenças regionais no acesso. Pacientes residentes das regiões norte e centro-oeste do país tiveram que percorrer maiores distâncias para alcançar os serviços (média ponderada = 296 a 870 km). A maioria dos hubs e polos de atração para atendimento oncológico foram identificados nas regiões Sudeste e Nordeste, sendo o município de Barretos o principal hub para todos os tipos de tratamento ao longo do tempo.As disparidades de acessibilidade para o tratamento de câncer, alertam para a necessidade de revisar a distribuição dos serviços de atenção especializada no país. A metodologia e os resultados apresentados neste estudo contribuem para as pesquisas sobre a melhoria do acesso ao tratamento do câncer e podem servir como referência para outros países, oferecendo dados relevantes para avaliação, monitoramento e planejamento estratégico de serviços oncológicos e de saúde em geral., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Objectives: To assess the correlation between the burden of seven priority neglected tropical diseases (NTDs) included in the Brazilian National Agenda of Priorities in Health Research - tuberculosis, Chagas disease, leprosy, malaria, leishmaniasis, dengue and schistosomiasis - and their respective research funding and output., Methods: This retrospective review obtained data on disease burden from the Global Burden of Disease Study and funding data from open access sources. Publications were retrieved from Scopus and SciELO, and characterised according to the type of research conducted. Correlation between funding, research output and burden was assessed by comparing the 'expected' and 'observed' values for funding and publications relative to the proportional burden for each disease., Results: There was an emphasis in basic biomedical research (average 30% of publications) and a shortage of health policy and systems (average 7%) and social sciences research (average 3%). Research output and funding were poorly correlated with disease burden. Tuberculosis, Chagas disease and schistosomiasis accounted for more than 75% of total NTD-related DALYs, but accounted for only 34% of publications. Leprosy, leishmaniasis and malaria, together, received 49% of NTD-related funding despite being responsible for only 9% of DALYs., Conclusions: The analysis evidenced a lack of correlation between disease burden, research output and government funding for priority NTDs in Brazil. Our findings highlight the importance of monitoring health needs, research investments and outputs to inform policy and optimise the uptake of evidence for action, particularly in developing countries, where resources are scarce and the research capacity is limited. The results contribute to health policy by highlighting the need for improving coordination of scientific activities and public health needs for effective impact., (© 2020 John Wiley & Sons Ltd.)

Background: Sporotrichosis has recently emerged as an important mycosis worldwide, with diverse transmission and epidemiologic profiles. For instance, in Brazil most cases are related to zoonotic transmission from naturally infected cats, and the majority of cases in China are due to external injury with environmental materials. Publications on sporotrichosis and on its etiologic agent may guide the direction of the research in this field. It can also define priorities for future studies. Methods: In this study, we evaluated the trends of global research in Sporothrix and sporotrichosis, based on publications records retrieved from Scopus and Web of Science databases for the period of 1945 to 2018. The overall productivity in the field, its geographical and temporal distribution, research themes, co-authorship networks, funding sources, and the implications of research findings for health practice were assessed using bibliometric approaches. Results: A total of 4,007 unique publications involving 99 countries were retrieved, most of them published after 2000. Authors based on institutions from the United States of America and Brazil accounted for 57.4% of the publications. Brazil was the leading country in terms of research collaboration and networking, with co-authorship with 45 countries. The thematic mapping revealed a temporal shift from clinical to applied research. Despite the large number of countries publishing in this field, most of funded studies came from Brazil, Mexico, China, South Africa, or the United States of America. The analysis of content identified few specific public health recommendations for prevention, case-management, or research. Moreover, most papers do not have a clearly defined intended audience. Conclusion: As the research in this field is emerging in several countries, with the generation of a large amount of data, it is necessary that scientists strengthen efforts to translate the research results into practice to curb this neglected infection., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Albuquerque PC et al.)

Background: Sporotrichosis has recently emerged as an important mycosis worldwide, with diverse transmission and epidemiologic profiles. For instance, in Brazil most cases are related to zoonotic transmission from naturally infected cats, and the majority of cases in China are due to external injury with environmental materials. Publications on sporotrichosis and on its etiologic agent may guide the direction of the research in this field. It can also define priorities for future studies. Methods: In this study, we evaluated the trends of global research in Sporothrix and sporotrichosis, based on publications records retrieved from Scopus and Web of Science databases for the period of 1945 to 2018. The overall productivity in the field, its geographical and temporal distribution, research themes, co-authorship networks, funding sources, and if audience and research findings are addressed in the abstracts. Results: A total of 4,007 unique publications involving 99 countries were retrieved, most of them published after 2000. Authors based on institutions from the United States of America and Brazil accounted for 57.4% of the publications. Brazil was the leading country in terms of research collaboration and networking, with co-authorship with 45 countries. The thematic mapping revealed a temporal shift from clinical to applied research. Despite the large number of countries publishing in this field, most of funded studies came from Brazil, Mexico, China, South Africa, or the United States of America. The analysis of content identified few specific public health recommendations for prevention, case-management, or research. Moreover, most papers do not have a clearly defined intended audience. Conclusion: As the research in this field is emerging in several countries, with the generation of a large amount of data, it is necessary that scientists strengthen efforts to translate the research results into practice to curb this neglected infection., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Albuquerque PC et al.)

Background: The recent Zika virus (ZIKAV) epidemics disclosed a major public health threat and a scientific and technological (S&T) challenge. The lessons learned from the S&T response of Latin America and the Caribbean (LAC) countries are critical to inform further research and guide scientific investments. The present study aimed to assess how new S&T knowledge produced and disseminated regionally can contribute to address global health challenges., Methods: Scientometric and social network analysis methods were used to assess the LAC scientific contribution and potential technological development on ZIKAV up to December 2017. ZIKAV-related publications were retrieved from the Web of Science, Scopus, and PubMed databases. Regionally published articles were obtained from SciELO (Scientific Electronic Library Online) and LILACS (Literature in the Health Sciences in Latin America and the Caribbean) databases. Patent registries were retrieved using Orbit Intelligence and Derwent Innovation. Records from each database were individually downloaded, integrated, standardized and analyzed., Results: We retrieved 5421 ZIKAV-related publications, revealing a sharp increase from 2015 onwards. LAC countries accounted for 20% of all publications and Brazil was among the top three most central countries in the global network for ZIKAV research. A total of 274 patent families backed up by experimental evidence were retrieved. Only 5% were filed by LAC assignees, all of them based in Brazil. The largest contribution of LAC research was on the clinical manifestations of the ZIKAV infection, along with vector control, which was also the main focus of patents., Conclusions: Our analysis offered a comprehensive overview of ZIKAV's research and development and showed that (i) LAC countries had a key role in generating and disseminating scientific knowledge on ZIKAV; (ii) LAC countries have expressively contributed to research on ZIKAV clinical manifestations; (iii) the Brazilian scientific community was potentially very effective in knowledge sharing and diffusion in the ZIKAV research network; (iv) Brazil was the single LAC country filing patents, mostly represented by independent inventors and low-tech patents. The paper advocates the need for a continued interdisciplinary approach to improve LAC countries ability to prevent, prepare for and control future outbreaks.

Introduction: Countries have traditionally been split into two major groups: developed or industrialized ("the North") and developing or underdeveloped ("the South"). Several authors and organizations have challenged this classification to recognize countries that have reached an intermediate stage of social and economic development. As proposed by Morel and collaborators in 2005, the concept of Innovative Developing Countries (IDCs) defines a group of nations with impactful scientific programs. Here, IDCs are reexamined by a variety of metrics to highlight their role in health innovation through research and development (R&D) programs on neglected tropical diseases (NTDs) that also positively impact epidemic preparedness., Results: To address the global changes due to expanding globalization we updated the original indicator of the number of USPTO patents deposited by individual countries per GDP and per capita to the number of international patents applications, related to applicant residence and deposited under the Patent Cooperation Treaty (PCT) per GNI (or GDP) and per capita. A comparison of the originally described ranking of top innovative countries to those in the present study revealed new members that updated the list of IDCs and showed a prominent role now played by China. Analyzing scientific publications in international journals since the introduction of the IDC concept in 2005 we found that IDCs do prioritize Neglected Tropical Diseases (NTDs) as an area of research. Finally we investigated the role of IDCs in two major public health emergencies between 2012 and 2016, the outbreaks of Ebola in West Africa and Zika in South America. An analysis of the co-authorship country networks demonstrated an important role for IDC infrastructure and personnel in the prevention and control of these epidemics., Discussion and Conclusions: Different techniques can be used to evaluate and measure innovative performance of countries. Country rankings published by traditional indexes, such as the Bloomberg Innovation Index (BII) and the Global Innovation Index (GII), only include high income economies among the top 20 performers. This is in sharp contrast to our approach, which identified 8-9 IDCs among the first 25 with China occupying the top position. Through an analysis of the pros and cons of the different methodologies, the IDC concept challenges more conventional approaches to address and estimate the innovative capacity of countries., Competing Interests: The authors have declared that no competing interests exist.

The concentrations of Cu, Cd, Pb, Zn, and Hg in diploid and triploid oysters from three farms (Guasave, Ahome, and Navolato) on the north-central coast of Sinaloa, Mexico, were assessed based on samples recovered during a single culture cycle 2013-2014. Metal burdens were more strongly correlated (p < 0.05) with the location of the farm than with either the ploidy or the interaction of both variables. The metal concentration ranking for oysters of both ploidies from the three farms was Zn > Cu > Cd > Pb > Hg. For all three farms, the mean concentrations of Cd and Pb in Crassostrea gigas were high, ranging from 2.52 to 7.98 μg/g wet weight for Cd and from 0.91 to 2.83 μg/g wet weight for Pb. Diploid and triploid oysters from the Guasave farm contained high levels of Cu (76.41 and 68.97 μg/g wet weight, respectively). Cu, Cd, and Zn were highly correlated (p < 0.05), and their concentrations may be influenced by agrochemical inputs. The mean levels of Cu for the Guasave farm and of Cd and Pb for all three farms exceeded permissible limits and represented a threat to human health during the sampling period (July 2014 to July 2014).

The NFAT family of transcription factors plays a central role in the regulation of cytokine gene expression during the immune response. NFAT functions have been extensively explored in lymphocyte activation and differentiation, but the involvement of NFAT proteins in dendritic cells (DCs) is still not well known. Here, we investigated the role of the NFAT1 transcription factor in murine DCs. Initially, we demonstrated by western blot that the NFAT1 protein is present in splenic DCs and is rapidly activated upon calcium influx. We then used NFAT1-deficient mice (NFAT1-/-) to investigate whether NFAT1 influences the ability of DCs to induce Th differentiation. Our data demonstrated that NFAT1-/- DCs showed an increased capacity to differentiate CD4 T cells to the Th1 phenotype. CD4 cells that were primed in vitro with NFAT1-/- DCs had increased IFN-γ production. The same results were observed when the CD4 cells were primed in vivo through the sensitization of NFAT1-/- mice with ovalbumin. Furthermore, our results demonstrated that the cytokine IL-12 is one of the factors involved in this process because its production is increased in NFAT1-/- mice, and neutralizing anti-IL-12 antibodies almost completely eliminated the IFN-γ production. These results demonstrated that the NFAT1 transcription factor regulates specific functions in DCs that are involved in CD4 differentiation, suggesting that the inhibition of NFAT1 in DCs may be used as a therapy to modulate specific immune responses., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

In Brazil, malaria is prevalent in the Amazon region and these regions coincide with high prevalence of intestinal parasites but few studies explore the interaction between malaria and other parasites. Therefore, the present study evaluates changes in cytokine, chemokine, C-reactive protein, and nitric oxide (NO) concentrations in 264 individuals, comparing plasma from infected individuals with concurrent malaria and intestinal parasites to individuals with either malaria infection alone and uninfected. In the studied population 24% of the individuals were infected with Plasmodium and 18% coinfected with intestinal parasites. Protozoan parasites comprised the bulk of the intestinal parasites infections and subjects infected with intestinal parasites were more likely to have malaria. The use of principal component analysis and cluster analysis associated increased levels of IL-6, TNF-α, IL-10, and CRP and low levels of IL-17A predominantly with individuals with malaria alone and coinfected individuals. In contrast, low levels of almost all inflammatory mediators were associated predominantly with individuals uninfected while increased levels of IL-17A were associated predominantly with individuals with intestinal parasites only. In conclusion, our data suggest that, in our population, the infection with intestinal parasites (mainly protozoan) does not modify the pattern of cytokine production in individuals infected with P. falciparum and P. vivax.

Hepatitis C virus (HCV) infection is a major burden to public health worldwide, affecting approximately 3% of the human population. Although HCV detection is currently based on reliable tests, the field of medical diagnostics has a growing need for inexpensive, accurate, and quick high-throughput assays. By using the recombinant HCV antigens NS3, NS4, NS5, and Combined, we describe a new bead-based multiplex test capable of detecting HCV infection in human serum samples. The first analysis, made in a singleplex format, showed that each antigen coupled to an individual bead set presented high-level responses for anti-HCV-positive reference serum pools and lower-level responses for the HCV-negative pools. Our next approach was to determine the sensitivity and specificity of each antigen by testing 93 HCV-positive and 93 HCV-negative sera. When assayed in the singleplex format, the NS3, NS4, and NS5 antigens presented lower sensitivity values (50.5%, 51.6%, and 55.9%, respectively) than did the Combined antigen, which presented a sensitivity of 93.5%. All antigens presented 100% specificity. These antigens were then multiplexed in a 4-plex assay, which resulted in increased sensitivity and specificity values, performing with 100% sensitivity and 100% specificity. The positive and negative predictive values for the 4-plex assay were 100%. Although preliminary, this 4-plex assay showed robust results that, aligned with its small-sample-volume requirements and also its cost- and time-effectiveness, make it a reasonable alternative to tests currently used for HCV screening of potentially infected individuals.

Background: Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2-1 can elicit the anti-inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2-1., Objective: We tested the hypothesis that JMF2-1 would prevent allergen-induced lung inflammation and airway hyperresponsiveness (AHR) by modulating T cell function in vivo and in vitro. Methods Local and systemic changes in leucocyte levels, cytokine production and lung mechanics were examined in a murine model of lung inflammation. JMF2-1 (0.05-2%) or saline was aerosolized twice a day during the ovalbumin (OVA)-provocation period (19-21 days post-sensitization). Analyses were performed 24 h after the final challenge. Primary cultured lymph node cells were used to assess the effects of JMF2-1 (100-600 μm) at the cellular level., Results: OVA challenge resulted in lung recruitment of CD4(+) T cells and eosinophils, increased generation of inflammatory cytokines and AHR to inhaled methacholine within 24 h. These changes were prevented by JMF2-1 nebulization, and occurred in parallel with an increase in the number of apoptotic cells in the lung. JMF2-1 treatment did not alter levels of CD4(+) or CD8(+) T cells in the thymus or lymph nodes of naïve mice, although it inhibited OVA-induced IL-13 production and the lymphocyte proliferative response in vitro. It also induced apoptosis of OVA-activated lymphocytes in a mechanism sensitive to z-VAD, indicating that JMF2-1 mediates caspase-dependent apoptosis., Conclusion: Inhalation of JMF2-1 prevents the cardinal features of asthma by reducing T(H) 2 cytokine generation and lung eosinophilic inflammatory infiltrates via local inhibition of T cell function and survival. JMF2-1 may represent a novel therapeutic alternative for asthma control with distinct advantages over local anaesthetics., (© 2011 Blackwell Publishing Ltd.)

Allergic asthma is a chronic inflammatory disease of the lung whose incidence and morbidity continues to rise in developed nations. Despite being a hallmark of asthma, the molecular mechanisms that determine airway hyperresponsiveness (AHR) are not completely established. Transcription factors of the NFAT family are involved in the regulation of several asthma-related genes. It has been shown that the absence of NFAT1 leads to an increased pleural eosinophilic allergic response accompanied by an increased production of Th2 cytokines, suggesting a role for NFAT1 in the regulation of allergic diseases. Herein, we analyze NFAT1-/- mice to address the role of NFAT1 in a model of allergic airway inflammation and its influence in AHR. NFAT1-/- mice submitted to airway inflammation display a significant exacerbation of several features of the allergic disease, including lung inflammation, eosinophilia, and serum IgE levels, which were concomitant with elevated Th2 cytokine production. However, in spite of the increased allergic phenotype, NFAT1-/- mice failed to express AHR after methacholine aerosol. Refractoriness of NFAT1-/- mice to methacholine was confirmed in naïve mice, suggesting that this refractoriness occurs in an intrinsic way, independent of the lung inflammation. In addition, NFAT1-/- mice exhibit increased AHR in response to serotonin inhalation, suggesting a specific role for NFAT1 in the methacholine pathway of bronchoconstriction. Taken together, these data add support to the interpretation that NFAT1 acts as a counterregulatory mechanism to suppress allergic inflammation. Moreover, our findings suggest a novel role for NFAT1 protein in airway responsiveness mediated by the cholinergic pathway.

Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF(-/-) mice occurs regardless of high concentrations of IL-4 in the lung and OVA-specific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF(-/-) mice compared to WT, but were reduced in the spleen of MIF(-/-), thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4(+) cells with anti-CD3 antibody demonstrated that MIF(-/-) cells produced increased amounts of IFN-gamma and IL-4 compared to WT CD4(+) cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma.

CD8+ T lymphocytes are excellent sources of IFN-gamma; however, the molecular mechanisms that dictate IFN-gamma expression upon TCR stimulation in these cells are not completely understood. In this study, we evaluated the involvement of NFAT1 in the regulation of IFN-gamma gene expression in murine CD8+ T cells and its relevance during Th differentiation. We show that CD8+, but not CD4+, T cells, represent the very first source of IFN-gamma upon primary T cell activation, and also that the IFN-gamma produced by naive CD8+ T cells may enhance CD4+ Th1 differentiation in vitro. TCR stimulation rapidly induced IFN-gamma expression in CD8+ T lymphocytes in a cyclosporin A-sensitive manner. Evaluation of CD8+ T cells showed that calcium influx alone was sufficient to activate NFAT1 protein, transactivate IFN-gamma gene promoter, and induce IFN-gamma production. In fact, NFAT1-deficient mice demonstrated highly impaired IFN-gamma production by naive CD8+ T lymphocytes, which were totally rescued after retroviral transduction with NFAT1-encoding vectors. Moreover, NFAT1-dependent IFN-gamma production by the CD8+ T cell compartment was crucial to control a Th2-related response in vivo, such as allergic inflammation. Consistently, CD8alpha- as well as IFN-gamma-deficient mice did not mount a Th1 immune response and also developed in vivo allergic inflammation. Our results clearly indicate that IFN-gamma production by CD8+ T cells is dependent of NFAT1 transcription factor and may be an essential regulator of Th immune responses in vivo.

Allergic diseases have been closely related to Th2 immune responses, which are characterized by high levels of interleukin (IL) IL-4, IL-5, IL-9 and IL-13. These cytokines orchestrate the recruitment and activation of different effector cells, such as eosinophils and mast cells. These cells along with Th2 cytokines are key players on the development of chronic allergic inflammatory disorders, usually characterized by airway hyperresponsiveness, reversible airway obstruction, and airway inflammation. Accumulating evidences have shown that altering cytokine-producing profile of Th2 cells by inducing Th1 responses may be protective against Th2-related diseases such as asthma and allergy. Interferon-gamma (IFN-gamma), the principal Th1 effector cytokine, has shown to be crucial for the resolution of allergic-related immunopathologies. In fact, reduced production of this cytokine has been correlated with severe asthma. In this review, we will discuss the role of IFN-gamma during the generation of immune responses and its influence on allergic inflammation models, emphasizing its biologic properties during the different aspects of allergic responses.

The nuclear factor of activated T cells (NFAT) family of transcription factors has been primarily identified in immune cells; however, these proteins have been recently found to be functionally active in several other non-immune cell types. NFAT proteins are activated upon different stimuli that lead to increased intracellular calcium levels. Regardless of their widely known cytokine gene expression properties, NFATs have been shown to regulate other genes related to cell cycle progression, cell differentiation and apoptosis, revealing a broader role for these proteins in normal cell physiology. Several reports have addressed the participation of NFATs in many aspects of malignant cell transformation and tumorigenic processes. In this review, we will discuss the involvement of the different NFAT family members in the regulation of cell cycling, differentiation and tumor formation, and also its implications on oncogenesis. Better understanding the mechanisms by which NFATs regulate cell cycle and tumor-related events should be relevant for the development of rational anti-cancer therapies.