Study of the Epidemiological Profile of Tuberculosis and Coinfection of HIV-Seropositive Patients in a Reference Hospital in the State of Alagoas / Estudo do Perfil Epidemiológico da Tuberculose e Coinfecção de Pacientes Soropositivos para HIV em Hospital de Referência no Estado de Alagoas

Abstract Tuberculosis is a disease that has affected the population for more than centuries, it is caused by Mycobacterium tuberculosis with high incidence and prevalence in the population. In Brazil, active tuberculosis is the condition with the greatest impact on mortality in people living with the human immunodeficiency virus, since this part of the population is more likely to develop the disease. In this sense, in order to elucidate the epidemiological profile of patients coinfected with Tuberculosis/HIV, a retrospective study was carried out with a quantitative approach in a referral hospital in the care of these patients in the State of Alagoas. 956 cases of tuberculosis and HIV co-infection were reported, with a higher incidence in males (63.49%), in mixed race (82.42%) and in the age group corresponding to the economically active population, between 21 and 50 years (84,.08%). In addition, the pulmonary clinical form (73.95%) is predominant among the cases, with the peripheral lymph node (32.12%) being the most frequent among the extrapulmonary forms (19.87%). Regarding the clinical outcome of these patients, it was observed that there was a higher rate of treatment drop-out in patients reported with alcoholism, consequently reducing the cure rate of these patients. Therefore, it is evident that socioeconomic variables directly influence the incidence and outcome of patients co-infected with Tuberculosis/HIV and that despite the therapeutic advances and the existing support network, it is still a disease that generates negative impacts on the social development of the country. (AU)

Resumo A tuberculose é uma enfermidade que afeta a população há mais de séculos, é causada pelo Mycobacterium tuberculosis apresentando elevada incidência e prevalência na população. No Brasil, a tuberculose ativa é a condição de maior impacto na mortalidade em pessoas que vivem com o vírus da imunodeficiência humana, já que essa parcela da população apresenta uma maior probabilidade de desenvolver a doença. Nesse sentindo, a fim de elucidar o perfil epidemiológico dos pacientes coinfectados com Tuberculose/HIV, realizou-se um estudo retrospectivo com abordagem quantitativa em um hospital de referência no atendimento destes pacientes no Estado de Alagoas. Foram notificados 956 casos de coinfecção tuberculose e HIV, apresentando maior incidência no sexo masculino (63,49%), na cor parda (82,42%) e na faixa etária correspondente a população economicamente ativa, entre 21 e 50 anos (84,08%). Além disso, a forma clínica pulmonar (73,95%) é predominante dentre os casos, sendo a ganglionar periférica (32,12%) a mais incidente entre as formas extrapulmonares (19,87%). Em relação ao desfecho clínico desses pacientes, observou-se que houve uma maior taxa de abandono do tratamento em pacientes notificados com agravo por alcoolismo, reduzindo consequentemente a taxa de cura destes pacientes. Portanto, fica evidente que variáveis socioeconômicas influenciam diretamente na incidência e no desfecho de pacientes coinfectados com Tuberculose/HIV e que apesar dos avanços terapêuticos e da rede de suporte já existente, ainda é uma doença que gera impactos negativos para o desenvolvimento social do país. (AU)

Analysis of the Role of Female Hormones During Infection by COVID-19.

Women have metabolic, immunological, and genetic variables that ensure more protection from coronavirus infection. However, the indication of treatment for several pathologies and contraception is determined by hormones that have adverse effects and raise doubts about their use during the COVID-19 pandemic. Therefore, the present study searches women specificities and the relation between female sexual hormones and COVID-19, and reports the main recommendations in this background. To this end, a review of the literature was conducted in the main databases, auxiliary data sources, and official websites. Therefore, considering the hypercoagulability status of COVID-19, the debate about the use of contraceptives due to the relative risk of thromboembolic effects that they impose arises. However, the current available evidence, as well as the recommendations of main health organs around the world, demonstrate that the use of hormonal contraceptives must be maintained during the pandemic.

As mulheres possuem variáveis metabólicas, imunológicas e genéticas que conferem maior proteção à infecção pelo coronavírus. Todavia, a indicação de tratamento para certas patologias e para a contracepção é determinada por hormônios que possuem efeitos adversos e levantam dúvidas quanto ao seu uso durante a pandemia da COVID-19. Desta forma, o presente estudo busca investigar as especificidades da mulher e a relação dos hormônios sexuais femininos com a COVID-19, assim como relatar as principais recomendações neste contexto. Para isso, realizou-se uma revisão da literatura nas principais bases de dados, fontes auxiliares de dados e sites oficiais. Portanto, considerando o estado hipercoagulável da COVID-19, surge o debate quanto à utilização de contraceptivos pelo seu risco relativo de efeitos tromboembólicos. No entanto, as atuais evidências disponíveis, assim como as recomendações dos principais órgãos de saúde do mundo, demonstraram que o uso de contraceptivos hormonais deve ser mantido durante a pandemia.

Analysis of the Role of Female Hormones During Infection by COVID-19 / Análise do papel dos hormônios femininos durante a infecção por COVID-19

Abstract Women have metabolic, immunological, and genetic variables that ensure more protection from coronavirus infection. However, the indication of treatment for several pathologies and contraception is determined by hormones that have adverse effects and raise doubts about their use during the COVID-19 pandemic. Therefore, the present study searches women specificities and the relation between female sexual hormones and COVID-19, and reports the main recommendations in this background. To this end, a review of the literature was conducted in the main databases, auxiliary data sources, and official websites. Therefore, considering the hypercoagulability status of COVID-19, the debate about the use of contraceptives due to the relative risk of thromboembolic effects that they impose arises. However, the current available evidence, as well as the recommendations of main health organs around the world, demonstrate that the use of hormonal contraceptives must be maintained during the pandemic.

Resumo As mulheres possuem variáveis metabólicas, imunológicas e genéticas que conferem maior proteção à infecção pelo coronavírus. Todavia, a indicação de tratamento para certas patologias e para a contracepção é determinada por hormônios que possuem efeitos adversos e levantam dúvidas quanto ao seu uso durante a pandemia da COVID-19. Desta forma, o presente estudo busca investigar as especificidades da mulher e a relação dos hormônios sexuais femininos com a COVID-19, assim como relatar as principais recomendações neste contexto. Para isso, realizou-se uma revisão da literatura nas principais bases de dados, fontes auxiliares de dados e sites oficiais. Portanto, considerando o estado hipercoagulável da COVID-19, surge o debate quanto à utilização de contraceptivos pelo seu risco relativo de efeitos tromboembólicos. No entanto, as atuais evidências disponíveis, assim como as recomendações dos principais órgãos de saúde do mundo, demonstraram que o uso de contraceptivos hormonais deve ser mantido durante a pandemia.

Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages.

We have previously described that arachidonic acid (AA)-5-lipoxygenase (5-LO) metabolism inhibitors such as NDGA and MK886, inhibit cell death by apoptosis, but not by necrosis, induced by extracellular ATP (ATPe) binding to P2X7 receptors in macrophages. ATPe binding to P2X7 also induces large cationic and anionic organic molecules uptake in these cells, a process that involves at least two distinct transport mechanisms: one for cations and another for anions. Here we show that inhibitors of the AA-5-LO pathway do not inhibit P2X7 receptors, as judged by the maintenance of the ATPe-induced uptake of fluorescent anionic dyes. In addition, we describe two new transport phenomena induced by these inhibitors in macrophages: a cation-selective uptake of fluorescent dyes and the release of ATP. The cation uptake requires secreted ATPe, but, differently from the P2X7/ATPe-induced phenomena, it is also present in macrophages derived from mice deficient in the P2X7 gene. Inhibitors of phospholipase A2 and of the AA-cyclooxygenase pathway did not induce the cation uptake. The uptake of non-organic cations was investigated by measuring the free intracellular Ca(2+) concentration ([Ca(2+)]i) by Fura-2 fluorescence. NDGA, but not MK886, induced an increase in [Ca(2+)]i. Chelating Ca(2+) ions in the extracellular medium suppressed the intracellular Ca(2+) signal without interfering in the uptake of cationic dyes. We conclude that inhibitors of the AA-5-LO pathway do not block P2X7 receptors, trigger the release of ATP, and induce an ATP-dependent uptake of organic cations by a Ca(2+)- and P2X7-independent transport mechanism in macrophages.

ATP-induced apoptosis involves a Ca2+-independent phospholipase A2 and 5-lipoxygenase in macrophages.

Macrophages express P2X(7) and other nucleotide (P2) receptors, and display the phenomena of extracellular ATP (ATP(e))-induced P2X(7)-dependent membrane permeabilization and cell death by apoptosis and necrosis. P2X(7) receptors also cooperate with toll-like receptors (TLRs) to induce inflammasome activation and IL-1beta secretion. We investigated signaling pathways involved in the induction of cell death by ATP(e) in intraperitoneal murine macrophages. Apoptosis (hypodiploid nuclei) and necrosis (LDH release) were detected 6h after an induction period of 20 min in the presence of ATP. Apoptosis was blocked by caspase 3 and caspase 9 inhibitors and by cyclosporin A. The MAPK inhibitors PD-98059, SB-203580 and SB-202190 provoked no significant effect on apoptosis, but SB-203580 blocked LDH release. Neither apoptosis nor necrosis was inhibited when both intra- and extracellular Ca(2+) were chelated during the induction period. Mepacrine, a generic PLA(2) inhibitor and BEL, an inhibitor of Ca(2+)-independent PLA(2) (iPLA(2)) blocked apoptosis, while pBPB and AACOOPF(3), inhibitors of secretory and Ca(2+)-dependent PLA(2) respectively, had no significant effect. Cycloxygenase inhibitors had no effect on apoptosis, while the inhibitors of lipoxygenase (LOX) and leukotriene biosynthesis nordihydroguaiaretic acid (NDGA), zileuton, AA-861, and MK-886 significantly decreased apoptosis. Neither NDGA nor MK-886 blocked apoptosis of 5-LOX(-/-) macrophages. CP-105696 and MK-571, antagonists of leukotriene receptors, had no significant effect on apoptosis. None of the inhibitors of PLA(2) and LOX/leukotriene pathway had a significant inhibitory effect on LDH release. Our results indicate that a Ca(2+)-independent step involving an iPLA(2) and 5-LOX are involved in the triggering of apoptosis but not necrosis by P2X(7) in macrophages.

Activation of ERK1/2 by extracellular nucleotides in macrophages is mediated by multiple P2 receptors independently of P2X7-associated pore or channel formation.

Macrophages express several P2X and P2Y nucleotide receptors and display the phenomenon of ATP-induced P2X7-dependent membrane permeabilization, which occurs through a poorly understood mechanism. Several P2 receptors are known to be coupled to the activation of mitogen-activated protein kinases (MAPKs) and Ca2+ signaling. Here, we use macrophages to investigate the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by nucleotides and the involvement of MAPKs and intracellular Ca2+ concentration in ATP-induced membrane permeabilization. Short-term (5 min) pre-exposure to oxidized ATP (oATP), a P2X7 antagonist that does not inhibit P2X7-associated inward currents or membrane permeabilization, inhibits the activation of ERK1/2 by ATP, ADP, the P2X7 agonist 2'-3'-O-(4-benzoylbenzoyl)-ATP (BzATP), but not by UTP and UDP. We conclude that macrophages display several P2Y receptors coupled to the ERK1/2 pathway and that oATP antagonizes the action of purine nucleotides, possibly binding to P2X7 and/or other purine-binding P2Y receptors. We also show that BzATP and ATP activate ERK1/2 by two different pathways since ERK1/2 activation by BzATP, but not by ATP, is blocked by the tryrosine kinase inhibitor, genistein, and the Src protein kinase inhibitor, tyrphostin. However, the activation of ERK1/2 by ATP is blocked by the protein kinase C (PKC) inhibitor, chelerythrine chloride. Under the same conditions, membrane permeabilization is not blocked by genistein, tyrphostin, or chelerythrine chloride, indicating that tyrosine kinase, Src protein kinase, and PKC are not required for pore opening. Membrane permeabilization is independent of ERK1/2 activation since chelerythrine, or short-term exposure to oATP or PD98059, efficiently block ERK1/2 activation without inhibiting membrane permeabilization. In addition, membrane permeabilization is not inhibited by SB203580 and SB202190, two inhibitors of p38 MAPK, nor by intracellular BAPTA, which blocks ATP-induced Ca2+ signals. These results suggest that multiple P2 receptors lead to ERK1/2 activation, that ligation of the same receptors by agonists with different affinities can lead to differential stimulation of separate pathways, and that MAPKs and intracellular Ca2+ fluxes are independent of P2X7-associated pore formation.