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RESUMEN El dengue es una infección viral transmitida a través del mosquito Aedes aegypti y presenta cuatro serotipos (DENV-1 a DENV-4). La enfermedad desencadena una variedad de manifestaciones clínicas, desde formas leves sin signos de alarma hasta formas graves, potencialmente mortales. Se presenta el caso de un niño de cinco años, procedente de la provincia del Callao, cuyos síntomas iniciales fueron fiebre, cefalea y malestar general. Al tercer día, el niño manifiestó dolor abdominal leve y vómitos escasos; posteriormente, distensión abdominal, ictericia y coluria. Fue hospitalizado en la unidad de cuidados intensivos pediátricos con deshidratación moderada, ictericia, edemas, abdomen distendido y doloroso, matidez desplazable, hígado a 2 cm debajo del reborde costal derecho y lúcido. Por exámenes complementarios, se evidenció falla hepática, hepatoesplenomegalia y derrame pleural en bases. Se diagnosticó dengue grave a través de una prueba de ELISA Ig M reactivo más sobreinfección por probable peritonitis bacteriana espontánea. Se inició el tratamiento con antibióticos, furosemida, plasma fresco congelado, crioprecipitado y metamizol. Al no observarse mejoría, se optimizó el diurético y se administró albúmina humana. Mostró mejoría con disminución de ascitis, edemas, ictericia y efusión pleural; también mejora del perfil hepático y de la coagulación, además de encontrarse afebril. Presentó inesperadamente dificultad respiratoria por insuficiencia cardiaca congestiva debido a miocardiopatía dilatada según ecocardiografía; se manejó con diuréticos. Fue dado de alta en estado afebril, sin edemas y con resolución de falla hepática y trastorno de coagulación.

ABSTRACT Dengue is a viral infection which is transmitted by the Aedes aegypti mosquito and has four serotypes (DENV-1 to DENV-4). The disease triggers a variety of clinical manifestations, ranging from mild forms without warning signs to severe lifethreatening forms. We present the case of a 5-year-old boy, from the province of Callao, whose first symptoms were fever, headache and general malaise. On the third day, the child had mild abdominal pain and little vomiting; subsequently, abdominal distension, jaundice and choluria. He was admitted to the pediatric intensive care unit being alert and with moderate dehydration, jaundice, edema, distended and tender abdomen, shifting dullness and liver 2 cm below the right costal margin. Complementary tests revealed liver failure, hepatosplenomegaly and pleural effusion in the bases. Using a reactive IgM ELISA, severe dengue was diagnosed, as well as a superinfection due to probable spontaneous bacterial peritonitis. He started treatment with antibiotics, furosemide, fresh frozen plasma, cryoprecipitate and metamizole. As the child did not get better, the diuretic was optimized, and human albumin was administered. Thereafter, he got better showing decreased ascites, edema, jaundice and pleural effusion; improvement of the liver and coagulation profile; and being afebrile. He unexpectedly presented respiratory distress due to congestive heart failure caused by dilated cardiomyopathy diagnosed by echocardiography; thus, he was treated with diuretics. The patient was discharged afebrile, without edema and with resolution of liver failure and coagulation disorder.

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The SUR1-TRPM4-AQP4 complex is overexpressed in the initial phase of edema induced after cerebral ischemia, allowing the massive internalization of Na+ and water within the brain micro endothelial cells (BMEC) of the blood-brain barrier. The expression of the Abcc8 gene encoding SUR1 depends on transcriptional factors that are responsive to oxidative stress. Because reactive oxygen species (ROS) are generated during cerebral ischemia, we hypothesized that antioxidant compounds might be able to regulate the expression of SUR1. Therefore, the effect of resveratrol (RSV) on SUR1 expression was evaluated in the BMEC cell line HBEC-5i subjected to oxygen and glucose deprivation (OGD) for 2 h followed by different recovery times. Different concentrations of RSV were administered. ROS production was detected with etidine, and protein levels were evaluated by Western blotting and immunofluorescence. Intracellular Na+ levels and cellular swelling were detected by imaging; cellular metabolic activity and rupture of the cell membrane were detected by MTT and LDH release, respectively; and EMSA assays measured the activity of transcriptional factors. OGD/recovery increased ROS production induced the AKT kinase activity and the activation of SP1 and NFκB. SUR1 protein expression and intracellular Na+ concentration in the HBEC-5i cells increased after a few hours of OGD. These effects correlated with cellular swelling and necrotic cell death, responses that the administration of RSV prevented. Our results indicate that the ROS/AKT/SP1-NFκB pathway is involved in SUR1 expression during OGD/recovery in BMEC of the blood-brain barrier. Thus, RSV prevented cellular edema formation through modulation of SUR1 expression.

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Resting membrane potential is a bioelectric property of all cells. Multiple players govern this property, the ion channels being the most important. Ion channel dysfunction can affect cells' resting membrane potential and could be associated with numerous diseases. Therefore, the drug discovery focus on ion channels has increased yearly. In addition to patch-clamp, cell-based fluorescent assays have shown a rapid and reliable method for searching new ion channel modulators. Here, we used a cell-based membrane potential assay to search for new blockers of the Kv10.1, a potassium channel strongly associated with cancer progression and a promising target in anticancer therapy. We found that fluoxetine and miconazole can inhibit the Kv10.1 channel in the micromolar range. In contrast, BL-1249 potentiates Kv10.1 currents in a dose-dependent manner, becoming the first molecule described as an activator of the channel. These results demonstrate that cell-based membrane potential assay can accelerate the discovery of new Kv10.1 modulators.

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Venoms from tarantulas contain low molecular weight vasodilatory compounds whose biological action is conceived as part of the envenomation strategy due to its propagative effects. However, some properties of venom-induced vasodilation do not match those described by such compounds, suggesting that other toxins may cooperate with these ones to produce the observed biological effect. Owing to the distribution and function of voltage-gated ion channels in blood vessels, disulfide-rich peptides isolated from venoms of tarantulas could be conceived into potential vasodilatory compounds. However, only two peptides isolated from spider venoms have been investigated so far. This study describes for the first time a subfraction containing inhibitor cystine knot peptides, PrFr-I, obtained from the venom of the tarantula Poecilotheria regalis. This subfraction induced sustained vasodilation in rat aortic rings independent of vascular endothelium and endothelial ion channels. Furthermore, PrFr-I decreased calcium-induced contraction of rat aortic segments and reduced extracellular calcium influx to chromaffin cells by the blockade of L-type voltage-gated calcium channels. This mechanism was unrelated to the activation of potassium channels from vascular smooth muscle, since vasodilation was not affected in the presence of TEA, and PrFr-I did not modify the conductance of the voltage-gated potassium channel Kv10.1. This work proposes a new envenomating function of peptides from venoms of tarantulas, and establishes a new mechanism for venom-induced vasodilation.

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ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines: resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagy/mitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance.

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BACKGROUND: The calcium-sensing receptor (CaSR) in the distal convoluted tubule (DCT) activates the NaCl cotransporter (NCC). Glucose acts as a positive allosteric modulator of the CaSR. Under physiologic conditions, no glucose is delivered to the DCT, and fructose delivery depends on consumption. We hypothesized that glucose/fructose delivery to the DCT modulates the CaSR in a positive allosteric way, activating the WNK4-SPAK-NCC pathway and thus increasing salt retention. METHODS: We evaluated the effect of glucose/fructose arrival to the distal nephron on the CaSR-WNK4-SPAK-NCC pathway using HEK-293 cells, C57BL/6 and WNK4-knockout mice, ex vivo perfused kidneys, and healthy humans. RESULTS: HEK-293 cells exposed to glucose/fructose increased SPAK phosphorylation in a WNK4- and CaSR-dependent manner. C57BL/6 mice exposed to fructose or a single dose of dapagliflozin to induce transient glycosuria showed increased activity of the WNK4-SPAK-NCC pathway. The calcilytic NPS2143 ameliorated this effect, which was not observed in WNK4-KO mice. C57BL/6 mice treated with fructose or dapagliflozin showed markedly increased natriuresis after thiazide challenge. Ex vivo rat kidney perfused with glucose above the physiologic threshold levels for proximal reabsorption showed increased NCC and SPAK phosphorylation. NPS2143 prevented this effect. In healthy volunteers, cinacalcet administration, fructose intake, or a single dose of dapagliflozin increased SPAK and NCC phosphorylation in urinary extracellular vesicles. CONCLUSIONS: Glycosuria or fructosuria was associated with increased NCC, SPAK, and WNK4 phosphorylation in a CaSR-dependent manner.

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Two sequential batch reactors (R1 and R2) of aerobic granular sludge (AGS) were inoculated with activated sludge of different origins. The objective was to investigate the granulation and the consistency between the structure of the microbial communities (16S rRNA amplicon sequencing) in each reactor and their metabolic performance (removal of C, N, and P). Both reactors were fed with acetate-based synthetic wastewater, targeting an anaerobic-aerobic cycle reputed to favor the phosphorus- and glycogen-accumulating organisms (PAO and GAO). Stable granulation was achieved in both reactors, where, instead of PAO, the dominant genera were ordinary heterotrophic organisms (OHO) such as Thauera, Paracoccus, and Flavobacterium known for their high capacity of aerobic storage of polyhydroxyalkanoates (PHA). Generally, there was good consistency between the metabolic behavior of each reactor and the bacterial genera detected. Both reactors showed high removals of C and complete nitrification (Nitrosomonas and Nitrospira detected) but a low level of simultaneous nitrification-denitrification (SND) during the aerated phase. The latter causes that nitrates were recycled to the initial phase, in detriment of PAO selection. Meanwhile, the study showed that selecting slow-growing OHOs (with aerobic storage capacity) favors stable granulation, revealing an alternative AGS technology for C and N removal.

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Objetivo: Describir la concentración de los anticuerpos neutralizantes detectados en el suero de profesionales de la salud que recibieron alguna de las vacunas contra el SARS-CoV-2, desarrollada por las empresas Sinopharm, Pfizer, Johnson & Johnson o el candidato vacunal de CureVac. Materiales y métodos: Investigación observacional, descriptiva, retrospectiva, de corte transversal. Se incluyeron en el estudio un total de 217 profesionales de la salud que recibieron el esquema completo de las vacunas de Sinopharm, Pfizer, Johnson & Johnson o del candidato de CureVac. A estos individuos se les había determinado la presencia de anticuerpos neutralizantes contra el SARS-CoV-2 en el suero mediante la técnica de inmunoensayo por electroquimioluminiscencia (eCLIA). Se consideraron las variables edad, sexo, antecedentes de infección con el SARS-CoV-2, concentración de anticuerpos neutralizantes y tipo de vacuna administrada. Resultados: El 16,60 % de los profesionales de la salud manifestó haber tenido COVID-19 antes de haber recibido la vacunación. Ellos se inmunizaron con las vacunas de Sinopharm (74,65 %), Pfizer (12,90 %), Johnson & Johnson (5,07 %) y el candidato de CureVac (7,37 %). Independientemente de la vacuna recibida, el 42,50 % de las personas sin infección previa que recibieron la vacuna no desarrollaron anticuerpos neutralizantes, mientras que el 16,70 % de los que sí tuvieron enfermedad previa no desarrolló estos anticuerpos. La vacuna de Pfizer indujo mayor concentración de anticuerpos neutralizantes (196,27 UA/mL) en pacientes con o sin infección previa. Conclusiones: El estudio confirma que la vacunación refuerza la inmunidad contra el nuevo coronavirus en individuos con diagnóstico previo de COVID-19, y sugiere que la vacuna desarrollada por Pfizer estimula de manera más eficaz la producción de anticuerpos neutralizantes.

Objective: To describe the concentration of neutralizing antibodies in serum from healthcare professionals who received any of the SARS-CoV-2 vaccines developed by Sinopharm, Pfizer or Johnson & Johnson, or CureVac's vaccine candidate. Materials and methods: An observational, descriptive, retrospective, cross-sectional research which included 217 healthcare professionals fully vaccinated with Sinopharm, Pfizer or Johnson & Johnson's vaccines, or CureVac's vaccine candidate. The presence of anti-SARS-CoV-2 neutralizing antibodies in serum was determined in these individuals using the electrochemiluminescence immunoassay (ECLIA). Variables such as age, sex, history of infection with SARS-CoV-2, concentration of neutralizing antibodies and brand of vaccine administered were considered. Results: Sixteen point six zero percent (16.60 %) of the healthcare professionals stated that they had already had COVID-19 before receiving the vaccine. They were immunized with the vaccines developed by Sinopharm (74.65 %), Pfizer (12.90 %) or Johnson & Johnson (5.07 %), or CureVac's vaccine candidate (7.37 %). Regardless of the vaccine received, 42.50 % of the individuals who had not been previously infected with SARS-CoV-2 and 16.70 % of those who had been previously infected did not develop neutralizing antibodies. Pfizer's vaccine produced the highest concentration of neutralizing antibodies (196.27 AU/mL) in patients with or without previous infection. Conclusions: The study demonstrates that vaccination boosts immunity in people previously infected with the novel coronavirus and suggests that Pfizer's vaccine produces the highest concentration of neutralizing antibodies.

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Municipal Wastewater Treatment Plants (MWWTPs) have proven to be sources of adverse environmental impacts; however, integrated management can help improve their efficiency. Therefore, this study aims to evaluate the gap between the current management and another based on an international standard applied to WWTPMs, in order to understand their environmental commitment, and to identify the challenges and opportunities they present for the adoption or certification of an environmental management system (EMS) based on ISO 14001. For this purpose, a descriptive cross-sectional study was carried out in two MWWTPs in southern Mexico. In a first step, an automated checklist was designed based on the requirements of the ISO 14001:2015 standard and based on a modified FMEA (Failure Mode and Effects Analysis) calculation method. In a second step, a diagnosis was carried out at the MWWTPs, followed by a SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis to determine internal and external factors until a series of challenges and opportunities was identified. The findings indicate that the selected MWWTPs have a wide gap that keeps them away from efficient management. Among the challenges, "limited financial resources" were identified followed by "high turnover of managerial staff", while the opportunities with the greatest potential for improvement are related to the factors "candidate for investment" and "environmental policy". The treatment plants show a weak environmental commitment, therefore rigorous action plans should be considered, not only to protect the environment but also the investment, and they should be the main promoters that challenge the private sector.

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RESUMEN En la pandemia por la COVID-19, las personas mayores son el grupo que concentra la mayor mortalidad, sobre todo quienes precisan de cuidados de largo plazo por haber perdido su habilidad funcional. Esta población vive en sus domicilios, con la familia o en un centro residencial. Se ha descrito que las personas mayores pueden desarrollar una forma de enfermedad oligosintomática o con una sintomatología clínica particular; por esta razón, las estrategias de tamizaje basadas en síntomas no son las más recomendables. Es necesario detectar de manera precoz a los enfermos en este grupo; por ello, analizamos y proponemos las mejores alternativas disponibles para conseguir este objetivo.

ABSTRACT During the COVID-19 pandemic, older people have been the group with the highest mortality rate, especially those who require long-term care for having lost their functional ability. These people are living at home with their family or in a nursing home. It has been described that older people may develop an oligosymptomatic SARS-CoV-2 infection or particular symptoms of the disease. Therefore, symptom-based screening is not the most recommended strategy in this scenario. Since it is necessary to detect early cases in the elderly population, this research work analyzes and proposes the best available alternatives for attaining such goal.

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OBJECTIVES: To assess changes in sleep parameters and circadian rhythm metrics measured by actigraphy in preschool-aged children. DESIGN: Longitudinal analysis over 1 year. PARTICIPANTS: Ninety-four children living in Tijuana and Ensenada, Mexico. MEASUREMENTS: Children wore accelerometers on the right hip for one continuous week at baseline and 1-year follow-up. Parents recorded child bedtime, waketime, and naps in sleep diaries. We used cosinor and nonparametric approaches to calculate circadian rhythm metrics. RESULTS: At baseline, children had a mean age of 4.2 years, and 51.1% were girls. In multivariable models adjusted for age, gender, BMI category, parental education, household income and city, at follow-up children had significantly earlier waketimes (ß = -7.99 minutes, p < .001) compared to baseline. Children also had lower sleep onset latency (ß = -2.32 minutes, p = .057), and longer nighttime sleep (ß = 9.38 minutes, p = .079), but these changes were not significant at the α < 0.05 level. We found significant increases in log relative amplitude (ß = 0.017, p = .009), and decreases in log midline estimated statistic of rhythm (ß = -0.084, p = .017) and log of the least active 5-hour period (ß = -0.057, p = .010). When we adjusted for co-sleeping, we found significant decreases in the number of nighttime awakenings (ß = -1.29, p = .011) but otherwise similar results. There were no other changes in sleep parameters or circadian rhythm metrics. CONCLUSIONS: Mean increases in nighttime sleep and earlier wake times over one year were concomitant with decreases in overall activity levels and increases in circadian rhythm robustness. Co-sleeping was a predictor of sleep disturbances. This study provides longitudinal evidence regarding changes in sleep and circadian metrics in a sample of children from an under-researched sociodemographic group during an important, early life period.

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BACKGROUND: Ion channels have been proposed as therapeutic targets for different types of malignancies. One of the most studied ion channels in cancer is the voltage-gated potassium channel ether-à-go-go 1 or Kv10.1. Various studies have shown that Kv10.1 expression induces the proliferation of several cancer cell lines and in vivo tumor models, while blocking or silencing inhibits proliferation. Kv10.1 is a promising target for drug discovery modulators that could be used in cancer treatment. This work aimed to screen for new Kv10.1 channel modulators using a thallium influx-based assay. METHODS: Pharmacological effects of small molecules on Kv10.1 channel activity were studied using a thallium-based fluorescent assay and patch-clamp electrophysiological recordings, both performed in HEK293 stably expressing the human Kv10.1 potassium channel. RESULTS: In thallium-sensitive fluorescent assays, we found that the small molecules loperamide and amitriptyline exert a potent inhibition on the activity of the oncogenic potassium channel Kv10.1. These results were confirmed by electrophysiological recordings, which showed that loperamide and amitriptyline decreased the amplitude of Kv10.1 currents in a dose-dependent manner. Both drugs could be promising tools for further studies. CONCLUSIONS: Thallium-sensitive fluorescent assay represents a reliable methodological tool for the primary screening of different molecules with potential activity on Kv10.1 channels or other K+ channels.

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Objetivo: Determinar la presencia y concentración de los anticuerpos neutralizantes en el suero de individuos que recibieron la vacuna contra el SARS-CoV-2 desarrollada por la empresa Sinopharm. Materiales y métodos: Investigación descriptiva y transversal. En el estudio se incluyeron 117 profesionales de la salud inoculados con dos dosis de la vacuna Sinopharm, en quienes se había detectado la presencia de anticuerpos neutralizantes contra SARS-CoV-2 en el suero mediante la técnica de inmunoensayo de electroquimioluminiscencia (eCLIA). Las variables consideradas en el estudio fueron la edad, el sexo, la concentración de anticuerpos neutralizantes y el antecedente de haber tenido COVID-19. Resultados: Se evidenció el incremento significativo de la concentración de anticuerpos neutralizantes en las personas que recibieron la vacuna y tuvieron una infección previa por SARS-CoV-2 (p < 0,001) respecto a las que se vacunaron, pero no presentaron infección previa. Conclusiones: El estudio evidencia que la vacunación refuerza la inmunidad contra el nuevo coronavirus en los pacientes con diagnóstico previo de COVID-19 y sugiere la relevancia de la aplicación de una tercera dosis de esta vacuna.

Objective: To describe the presence and the concentration of neutralizing antibodies at serum of healthcare professionals inoculated with the Sinopharm anti-SARS-CoV2 vaccine. Materials and methods: Descriptive and transversal research. A total of 117 healthcare professionals inoculated with two doses of the Sinopharm vaccine having quantitative data of neutralizing antibodies at serum (detected by eCLIA) were included. Age, sex, neutralizing antibodies concentration and previous diagnostic of COVID-19 diseases were the variables. Results: A significant increase on neutralizing antibodies concentration were detected on pre- COVID-19 vaccinated persons regarding those vaccinated without previous diagnostic of the viral infection (p < 0,001). Conclusions: the study evidence that Sinopharm vaccine boost immunity against the new coronavirus on previously infected persons and suggest that a third dose of the vaccine could be relevant to boost the immune response.

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Sperm capacitation is essential to gain fertilizing capacity. During this process, a series of biochemical and physiological modifications occur that allow sperm to undergo acrosomal exocytosis (AE). At the molecular level, hyperpolarization of the sperm membrane potential (Em) takes place during capacitation. This study shows that human sperm incubated under conditions that do not support capacitation (NC) can become ready for an agonist stimulated AE by pharmacologically inducing Em hyperpolarization with Valinomycin or Amiloride. To investigate how Em hyperpolarization promotes human sperm's ability to undergo AE, live single-cell imaging experiments were performed to simultaneously monitor changes in [Ca2+ ]i and the occurrence of AE. Em hyperpolarization turned [Ca2+ ]i dynamics in NC sperm from spontaneously oscillating into a sustained slow [Ca2+ ]i increase. The addition of progesterone (P4) or K+ to Valinomycin-treated sperm promoted that a significant number of cells displayed a transitory rise in [Ca2+ ]i which then underwent AE. Altogether, our results demonstrate that Em hyperpolarization is necessary and sufficient to prepare human sperm for the AE. Furthermore, this Em change decreased Ca2+ oscillations that block the occurrence of AE, providing strong experimental evidence of the molecular mechanism that drives the acquisition of acrosomal responsiveness.

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RESUMEN Desde su aparición en diciembre de 2019, la infección por SARS-CoV-2 se expandió rápidamente a todo el mundo. Aproximadamente, el 80 % de pacientes con COVID-19 presentan síntomas leves a moderados, el 20 % desarrolla cuadros respiratorios graves, y alrededor del 6 % pueden requerir ventilación mecánica. En ausencia de pautas terapéuticas comprobadas, varios medicamentos ya conocidos empezaron a ser evaluados por sus probables beneficios en el tratamiento de COVID-19. Entre ellos, está el fármaco antiparasitario ivermectina, una de las avermactinas producidas por la bacteria Streptomyces avermitilis, que fue descubierta en los años setenta por el grupo del profesor Omura, en colaboración con la industria farmacéutica. Se ha demostrado que la ivermectina inhibe la interacción entre la proteína viral y el heterodímero de importina α/β1, lo que provoca la inhibición de la replicación del virus. Recientemente, este mecanismo de acción de la ivermectina frente al SARS-CoV-2 fue demostrado en células Vero/hSLAM. A la fecha, se conocen los resultados de un ensayo clínico en Argentina que comprueba la utilidad de la ivermectina en las etapas tempranas de la enfermedad; asimismo, en el mundo se registran alrededor de 40 estudios clínicos que buscan confirmar su importancia como un tratamiento costo-efectivo para COVID-19. Respecto a la seguridad, en estos años la ivermectina ha demostrado ser un fármaco bien tolerado.

ABSTRACT Since its appearance in December 2019, the SARS-CoV-2 infection spread rapidly to the whole world. About 80 % of COVID-19 patients have mild to moderate symptoms, 20 % develop severe respiratory symptoms, and about 6 % may require mechanical ventilation. In the absence of clinically proven treatment guidelines, several well-known drugs began to be evaluated in clinical trials for their likely benefits in the treatment of COVID-19. Among them is the antiparasitic drug ivermectin, one of the avermactins produced by the bacterium Streptomyces avermitilis, discovered in the seventies by Professor Omura's group in collaboration with the pharmaceutical industry. Ivermectin has been shown to inhibit the interaction between viral protein and importin α/β1 heterodimer, leading to inhibition of viral replication. This mechanism of action of ivermectin against SARS-CoV-2 was recently demonstrated in Vero/hSLAM cells. To date, the results of a clinical trial conducted in Argentina that prove the usefulness of ivermectin in the early stages of the disease are known. In addition, around 40 clinical studies, which seek to confirm the importance of ivermectin as a cost-effective treatment for COVID-19, are registered worldwide. Regarding its safety, ivermectin has proven to be a well-tolerated drug over the years.

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Nociceptive stimuli attributes are codified in the periphery; at this level, D2-like dopamine (DA) receptor activation decreases the high voltage-gated Ca2+ current predominantly in mechanonociceptive neurons, which explains the presynaptic action mechanism of the antinociception produced by quinpirole when it is intrathecally administered in rats. However, the identity of D2-like DA receptor subtype that mediates this effect remains unknown. To answer this question, we used Fluo-4-based Ca2+ microfluorometry to study the depolarization-elicited [Ca2+]i increase in small non-peptidergic DRG neurons (identified by its binding to the Isolectin B4), and to test the effect of D2-like DA receptor activation by quinpirole in presence of selective antagonists for D2, D3, and D4 DA receptors. The results showed a significantly greater contribution of the D4 DA receptor in the down-modulation of depolarization-elicited [Ca2+]i increase in small non-peptidergic DRG neurons compared to the other receptors. Although the D2 and D3 receptor antagonists also slightly inhibited the effect of quinpirole, their effects were significantly weaker than those of the D4 receptor antagonist. Furthermore, we showed that quinpirole selectively inhibits the CaV2.2 Ca2+ channels. Our results suggest that the activation of the D4 DA receptors is a promising strategy for pain management at the spinal cord level.

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RESUMEN La nueva pandemia de COVID-19 causada por el virus SARS-CoV-2 desafía actualmente a la humanidad. Este virus originario de murciélagos ha sido transmitido a humanos, probablemente, a través del pangolín en el mercado marino de Wuhan (China) a fines del 2019. Se disemina por gotitas de saliva o a través de materiales contaminados, por lo que es sumamente importante aislar a las personas infectadas que pueden ser sintomáticas o asintomáticas. El cuadro clínico típico se caracteriza por fiebre, tos seca, dificultad respiratoria y malestar general. Este integrante de la familia de los coronavirus tiene mayor capacidad infectiva que sus predecesores, pero una menor mortalidad (2-3 %). Las pruebas de laboratorio para detectar la presencia del virus se basan en la reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR, por su sigla en inglés) o en inmunoensayos.

ABSTRACT The novel COVID-19 pandemic caused by the SARS-CoV-2 virus is currently challenging humankind. This virus originated in bats has probably been transmitted to humans through pangolins in the Wuhan marine market (China) by the end of 2019. It is spread by droplets of saliva or through contaminated materials, making it extremely important to isolate infected people who may be symptomatic or asymptomatic. The typical clinical features of this disease are fever, dry cough, shortness of breath and general malaise. This member of the coronavirus family shows higher infectivity but lower mortality rates (2-3 %) than its predecessors. Laboratory tests to detect the virus include reverse transcriptase-polymerase chain reaction (RT-PCR) tests or immunoassays.

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RESUMEN La humanidad se enfrenta, en la actualidad, a un reto que no diferencia fronteras, ideologías, sistemas socioeconómicos, etnias, religiones o culturas. Es una guerra que nos une como especie biológica, en la que las armas fundamentales provienen de la investigación puesta al servicio de los sistemas de salud. En esta guerra los gobiernos y las organizaciones internacionales de salud definen la estrategia; mientras que los sistemas de salud y las fuerzas del orden, de la mano de la ciudadanía, concretan las acciones y libran cada una de las batallas. Sin embargo, el más importante de los enfrentamientos se realiza en el interior de cada uno de nosotros. Como Perseo enfrentó a Hades en una batalla de titanes para evitar que convirtiera la Tierra en un infierno, el sistema inmune pone en marcha una poderosa maquinaria en la que moléculas y células del sistema innato y adquirido actúan de manera coordinada para combatir al SARS-CoV-2. Una maquinaria que sigue un guion escrito por la evolución, y que deja en nuestro sistema de defensa una memoria que nos fortalecerá como especie para enfrentar futuros Hades. Este trabajo resume la valiosa información que se ha publicado en los últimos meses respecto al coronavirus SARS-CoV-2 en su interacción con el sistema inmune. Se incluyen aspectos relacionados con la detección de la respuesta inmune como herramienta para el diagnóstico de esta infección, y la manipulación del sistema inmune en la prevención o el tratamiento de la misma.

ABSTRACT Humankind is currently facing a challenge that distinguishes no borders, ideologies, socioeconomic systems, ethnic groups, religions or cultures. It is a war that unites us as a biological species, in which the main weapons come from research aimed at improving health systems. In this war, governments and international health organizations define the strategy; and health systems and law enforcement agencies, together with citizens' support, carry out actions and fight the battles. However, the most important battle is fought inside each of us. Just like Perseus fought against Hades in a battle of titans to prevent the Earth from turning into hell, the immune system activates a powerful machinery in which molecules and cells of the innate and acquired immune system jointly act to defeat SARS-Cov-2: a machinery that follows a script written by evolution, and that will leave in our immune system a memory that will strengthen us as a species to face future Hades. This work summarizes valuable information published in recent months regarding the interaction between SARS-Cov-2 and the immune system. It also includes aspects related to the detection of the immune response as a tool for the diagnosis of this infection, as well as the manipulation of the immune system to prevent or treat the disease.

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RESUMEN En diciembre de 2019, China se convirtió en el centro de un brote de neumonía de causa desconocida que atrajo la atención mundial. Se trataba del nuevo coronavirus 2019 (2019-nCoV o SARS-CoV-2) que se ha expandido rápidamente. Hasta el 31 de marzo de 2020 se han reportado alrededor de 800 000 casos y 38 714 muertes en el mundo. En el Perú, se han informado 950 casos y 24 fallecidos. Se ha observado que el virus afecta con mayor frecuencia a adultos mayores, personas inmunocomprometidas o con comorbilidades. En esta revisión ofrecemos una vista panorámica de los conocimientos actuales relacionados con las alternativas terapéuticas para la COVID-19, desde fármacos con comprobada actividad antiviral que se han utilizado regularmente en otras enfermedades (arbidol, remdesivir, lopinavir/ritonavir, favipiravir) hasta medicamentos que usualmente han sido empleados como antiparasitarios (cloroquina e hidroxicloroquina) o antibacterianos (teicoplanina y azitromicina), pero que en la coyuntura actual retoman notoriedad por su posible y potencial eficacia frente a este virus. Asimismo, se resaltan los esquemas terapéuticos incluidos recientemente en la norma técnica emitida por el Ministerio de Salud en Perú (cloroquina, hidroxicloroquina e hidroxicloroquina/azitromicina). Si bien se han logrado avances importantes en la determinación de potenciales alternativas terapéuticas farmacológicas, es necesario realizar ensayos controlados aleatorizados para determinar la seguridad y la eficacia de medicamentos para el tratamiento de pacientes con COVID-19.

ABSTRACT In December 2019, China became the center of a pneumonia outbreak of unknown cause that caught the world's attention. It was the new coronavirus 2019 (2019-nCoV or SARS-CoV-2), which has rapidly spread to the rest of the world. As of March 31, 2020, around 800,000 cases and 38,714 deaths have been reported worldwide. In Peru, 950 cases and 24 deaths have been reported. The virus has been found to affect most frequently elderly people, immunocompromised individuals or those with comorbidities. In this review article, we offer a comprehensive overview of current knowledge related to therapeutic alternatives for COVID-19, from drugs with proven antiviral activity that have been regularly used in other pathologies (arbidol, remdesivir, lopinavir/ritonavir, favipiravir) to drugs that have been usually used as antiparasitic (chloroquine and hydroxychloroquine) or antibacterial agents (teicoplanin and azithromycin), but nowadays have gained notoriety because of their possible and potential efficacy against COVID-19. Likewise, the therapeutic schemes recently included in the technical standard issued by the Ministry of Health of Peru (chloroquine, hydroxychloroquine and hydroxychloroquine/azithromycin) are highlighted. Although significant advances have been achieved in determining potential therapeutic alternatives, randomized controlled trials are needed to determine the safety and efficacy of medications for the treatment of patients with COVID-19.