Centro de Altos Estudios en Ciencias Humanas y de la Salud

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    A functional analysis of the cyclophilin repertoire in the protozoan parasite Trypanosoma cruzi
    (MDPI, 2018-10-31) Fuchs, Alicia Graciela ; Perrone, Alina E ; Milduberger, Natalia A. ; Bustos, Patricia L. ; Bua, Jaqueline
    Trypanosoma cruzi is the etiological agent of Chagas disease. It affects eight million people worldwide and can be spread by several routes, such as vectorborne transmission in endemic areas and congenitally, and is also important in non-endemic regions such as the United States and Europe due to migration from Latin America. Cyclophilins (CyPs) are proteins with enzymatic peptidyl-prolyl isomerase activity (PPIase), essential for protein folding in vivo. Cyclosporin A (CsA) has a high binding affinity for CyPs and inhibits their PPIase activity. CsA has proved to be a parasiticidal drug on some protozoa, including T. cruzi. In this review, we describe the T. cruzi cyclophilin gene family, that comprises 15 paralogues. Among the proteins isolated by CsA-affinity chromatography, we found orthologues of mammalian CyPs. TcCyP19, as the human CyPA, is secreted to the extracellular environment by all parasite stages and could be part of a complex interplay involving the parasite and the host cell. TcCyP22, an orthologue of mitochondrial CyPD, is involved in the regulation of parasite cell death. Our findings on T. cruzi cyclophilins will allow further characterization of these processes, leading to new insights into the biology, the evolution of metabolic pathways, and novel targets for anti-T. cruzi contro
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    A homolog of cyclophilin D is expressed in Trypanosoma cruzi and is involved in the oxidative stress–damage response
    (Cell Death Differentiation Association (ADMC), 2017-2-6) Bustos, Patricia L. ; Volta, Viviana J. ; Perrone, Alina E ; Milduberger, Natalia A. ; Bua, Jaqueline
    Mitochondria have an important role in energy production, homeostasis and cell death. The opening of the mitochondrial permeability transition pore (mPTP) is considered one of the key events in apoptosis and necrosis, modulated by cyclophilin D (CyPD), a crucial component of this protein complex. In Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, we have previously described that mitochondrial permeability transition occurs after oxidative stress induction in a cyclosporin A-dependent manner, a well-known cyclophilin inhibitor. In the present work, a mitochondrial parasite cyclophilin, named TcCyP22, which is homolog to the mammalian CyPD was identified. TcCyP22-overexpressing parasites showed an enhanced loss of mitochondrial membrane potential and loss of cell viability when exposed to a hydrogen peroxide stimulus compared with control parasites. Our results describe for the first time in a protozoan parasite that a mitochondrial cyclophilin is a component of the permeability transition pore and is involved in regulated cell death induced by oxidative stress
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    Alcohol hangover induces nitric oxide metabolism changes by impairing NMDA receptor-PSD95-nNOS pathway
    (Elsevier, 2021-5-5) Karadayian, Analía G. ; Bustamante, Juanita ; Lores-Arnaiz, Silvia
    Alcohol hangover is defined as the combination of mental and physical symptoms experienced the day after a single episode of heavy drinking, starting when blood alcohol concentration approaches zero. We previously evidenced increments in free radical generation and an imbalance in antioxidant defences in non-synaptic mitochondria and synaptosomes during hangover. It is widely known that acute alcohol exposure induces changes in nitric oxide (NO) production and blocks the binding of glutamate to NMDAR in central nervous system. Our aim was to evaluate the residual effect of acute ethanol exposure (hangover) on NO metabolism and the role of NMDA receptor-PSD95-nNOS pathway in non-synaptic mitochondria and synaptosomes from mouse brain cortex. Results obtained for the synaptosomes fraction showed a 37% decrease in NO total content, a 36% decrease in NOS activity and a 19% decrease in nNOS protein expression. The in vitro addition of glutamate to synaptosomes produced a concentration-dependent enhancement of NO production which was significantly lower in samples from hangover mice than in controls for all the glutamate concentrations tested. A similar patter of response was observed for nNOS activity being decreased both in basal conditions and after glutamate addition. In addition, synaptosomes exhibited a 64% and 15% reduction in NMDA receptor subunit GluN2B and PSD-95 protein expression, respectively. Together with this, glutamate-induced calcium entry was significant decreased in synaptosomes from alcohol-treated mice. On the other hand, in non-synaptic mitochondria, no significant differences were observed in NO content, NOS activity or nNOS protein expression. The expression of iNOS remained unaltered in synaptosomes and non-synaptic mitochondria. Here we demonstrated that hangover effects on NO metabolism are strongly evidenced in synaptosomes probably due to a disruption in NMDAR/PSD- 95/nNOS pathway.
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    Circulating cytokine and chemokine profiles of trypanosoma cruzi-infected women during pregnancy and its association with congenital transmission
    (Infectious Diseases Society of America (IDSA), 2021-9-15) Volta, Viviana J. ; Bustos, Patricia L. ; González, Carolina ; Natale, María Ailen ; Perrone, Alina E ; Milduberger, Natalia A. ; Laucella, Susana A. ; Bua, Jacqueline
    Background. Trypanosoma cruzi, the causative agent of Chagas disease, can be transmitted to the offspring of infected women, which constitutes an epidemiologically significant parasite transmission route in nonendemic areas. It is relevant to evaluate differ entially expressed factors in T. cruzi-infected pregnant women as potential markers of Chagas congenital transmission. Methods. Circulating levels of 12 cytokines and chemokines were measured by enzyme-linked immunosorbent assay or cytometric bead array in T. cruzi-infected and uninfected pregnant women in their second trimester of pregnancy and control groups of T. cruzi-infected and uninfected nonpregnant women. Results. Trypanosoma cruzi-infected women showed a proinflammatory Th1-biased profile, with increased levels of tumor ne crosis factor (TNF)-a, interleukin (IL)-12p70, IL-15, and monokine induced by interferon-gamma (MIG). Uninfected pregnant women presented a biased response towards Th2/Th17/Treg profiles, with increased plasma levels of IL-5, IL-6, IL-1ß, IL-17A, and IL-10. Finally, we identified that high parasitemia together with low levels of TNF-a, IL-15, and IL-17, low TNF-a/IL-10 ratio, and high IL-12p70 levels are factors associated with an increased probability of Chagas congenital transmission. Conclusions. Trypanosoma cruzi-infected pregnant women who did not transmit the infection to their babies exhibited a dis tinct proinflammatory cytokine profile that might serve as a potential predictive marker of congenital transmission.
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    Descripción de las características clínicas y epidemiológicas de las personas mayores de edad diagnosticadas de COVID-19 durante el año 2021 en el Departamento Rosario, Santa Fe, Argentina
    (Círculo Médico de Rosario, 2023) Weisburd, Guillermo Jaime ; Fernández, Florencia ; Gabini, Sebastián Manuel
    Objetivo: describir las características clínicas y epidemiológicas de las personas mayores de edad diagnosticadas de COVID-19 durante el año 2021 en el departamento Rosario, Santa Fe, Argentina. Estudio descriptivo, cuantitativo, transversal y retrospectivo. Los datos se recolectaron a partir de los registros oficiales del Ministerio de Salud de la Provincia de Santa Fe cargados en Sistema Integrado de Información Sanitaria Argentino. Se registraron un total de 111.095 casos confirmados. 69,4% se presentaron entre los meses de abril a julio. 51,4% eran mujeres y 48,6% varones. El promedio de edad fue de 42,82 años (DE = 15,94). Fueron internados 2.810 pacientes, 53,8% varones y 46,2% mujeres. 63,8% tenían más de 60 años. De los pacientes internados el 23,27% fueron derivados a la Unidad de Cuidados Intensivos (UCI) y 56% eran varones. De los pacientes internados el 93,1% presentó al menos una comorbilidad y ésta se comoprobó en 91,4% de los ingresados a la UCI. Hubo 1.962 decesos, el 56,8% fueron varones y el 74,6% en mayores de 60 años. La mayor cantidad de confirmados se presentó en la temporada otoño-invierno. Predominaron las mujeres y menores de 60 años. En los casos de gravedad y defunción preponderaron los varones mayores de 60 años y asociados a comorbilidad.
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    Descripción de las características clínicas y epidemiológicas de las personas mayores de edad diagnosticadas de COVID-19 durante el año 2021 en el Departamento Rosario, Santa Fe, Argentina
    (Círculo Médico de Rosario, 2023) Weisburd, Guillermo Jaime ; Fernández, Florencia ; Gabini, Sebastian Manuel
    Objetivo: describir las características clínicas y epidemiológicas de las personas mayores de edad diagnosticadas de COVID-19 durante el año 2021 en el departamento Rosario, Santa Fe, Argentina. Estudio descriptivo, cuantitativo, transversal y retrospectivo. Los datos se recolectaron a partir de los registros oficiales del Ministerio de Salud de la Provincia de Santa Fe cargados en Sistema Integrado de Información Sanitaria Argentino. Se registraron un total de 111.095 casos confirmados. 69,4% se presentaron entre los meses de abril a julio. 51,4% eran mujeres y 48,6% varones. El promedio de edad fue de 42,82 años (DE = 15,94). Fueron internados 2.810 pacientes, 53,8% varones y 46,2% mujeres. 63,8% tenían más de 60 años. De los pacientes internados el 23,27% fueron derivados a la Unidad de Cuidados Intensivos (UCI) y 56% eran varones. De los pacientes internados el 93,1% presentó al menos una comorbilidad y ésta se comoprobó en 91,4% de los ingresados a la UCI. Hubo 1.962 decesos, el 56,8% fueron varones y el 74,6% en mayores de 60 años. La mayor cantidad de confirmados se presentó en la temporada otoño-invierno. Predominaron las mujeres y menores de 60 años. En los casos de gravedad y defunción preponderaron los varones mayores de 60 años y asociados a comorbilidad.
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    Improved immuno-detection of a low-abundance cyclophilin allows the confirmation of its expression in a protozoan parasite
    (Hilaris, 2015-10-6) Bustos, Patricia L. ; Perrone, Alina E ; Milduberger, Natalia A. ; Bua, Jaqueline
    Protein samples can be challenging to analyze due to the presence of high-abundance proteins masking low abundance proteins of interest, such as biomarkers and novel physiological mediators. Cyclophilins are chaperones involved in the cis/trans isomerization of peptidyl-prolyl bonds in peptides or proteins and have been found in every organism sequenced to date. Although considerable progress has been made in the characterization of some cyclophilins expressed in diverse parasites invading humans, the main aspects of low-abundance members of this family remain unknown. In the present work, we present that the combined strategy of using more specific antibodies and increasing the presence of subcellular proteins in the sample, allowed us to confirm the expression of a 21.1 kDa cyclophilin for the first time in Trypanosoma cruzi.
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    Lactic acid transport mediated by aquaporin-9 : implications on the pathophysiology of preeclampsia
    (Frontiers, 2021) Acosta, Lucas Hernán ; Medina, Yollyseth ; Reppetti, Julieta ; Corominas, Ana ; Bustamante, Juanita ; Szpilbarg, Natalia ; Damiano, Alicia E.
    Aquaporin-9 (AQP9) expression is significantly increased in preeclamptic placentas. Since feto-maternal water transfer is not altered in preeclampsia, the main role of AQP9 in human placenta is unclear. Given that AQP9 is also a metabolite channel, we aimed to evaluate the participation of AQP9 in lactate transfer across the human placenta. Explants from normal term placentas were cultured in low glucose medium with or without L-lactic acid and in the presence and absence of AQP9 blockers (0.3 mM HgCl2 or 0.5 mM Phloretin). Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release. Apoptotic indexes were analyzed by Bax/Bcl-2 ratio and Terminal Deoxynucleotidyltransferase-Mediated dUTP Nick-End Labeling assay. Heavy/large and light/small mitochondrial subpopulations were obtained by differential centrifugation, and AQP9 expression was detected by Western blot. We found that apoptosis was induced when placental explants were cultured in low glucose medium while the addition of L-lactic acid prevented cell death. In this condition, AQP9 blocking increased the apoptotic indexes. We also confirmed the presence of two mitochondrial subpopulations which exhibit different morphologic and metabolic states. Western blot revealed AQP9 expression only in the heavy/large mitochondrial subpopulation. This is the first report that shows that AQP9 is expressed in the heavy/large mitochondrial subpopulation of trophoblasts. Thus, AQP9 may mediate not only the lactic acid entrance into the cytosol but also into the mitochondria. Consequently, its lack of functionality in preeclamptic placentas may impair lactic acid utilization by the placenta, adversely affecting the survival of the trophoblast cells and enhancing the systemic endothelial dysfunction.
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    Sexual health and sexual quality of life among individuals with spinal cord injury in Latin America
    (American Spinal Injury Association (ASIA), 2023) Longoni, Melina Noemi ; Ertl, Melissa E. ; Ramos-Usuga, Daniela Lucía ; Carballea, Denise ; Degano, Mariela ; Perrin, Paul P ; Arango-Lasprilla, Juan Carlos
    Background: Sexual changes are an area of primary concern for individuals with spinal cord injury (SCI) and their partners, but the topic has gone largely unexplored in the research literature. Objectives: This study examined how individuals with SCI in Latin America experience their sexuality and what issues they and their partners face in this area. Methods: A total of 248 individuals with SCI from Latin America completed an online 60-item survey regarding sexuality. Results: The majority of participants (87.7%) reported that they had noticed changes in sexuality after the injury, mainly physical problems (50.7%), emotional problems (38.7%), and changes in relationships with partners (27.5%). Regarding sexual desire, 47.2% indicated that desire remained the same after SCI. The majority of participants (81.9%) indicated not having received any information about sexuality after SCI during their hospital stay but reported that they would have liked to have received information (98.1%). Of all participants, 66.1% reported never having been asked about problems or difficulties in their sexual life after SCI by any health professional. Conclusion: Interventions designed to educate individuals with SCI regarding the effect of injury on their sexual functioning, responsiveness, and expression, as well as to support them in maintaining and enhancing their sexual well-being, may be extremely beneficial, particularly in Latin America. Findings highlight the distinct need for professionals to introduce the topic of sexuality by discussing it in a straightforward, nonjudgmental manner and to integrate discussions about sex and related issues into assessment, planning, and ongoing treatment.
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    Smooth versus textured implants and their association with the frequency of capsular contracture in primary breast augmentation
    (American Society of Plastic Surgery, 2022) Filiciani, Sandra ; Siemienczuk, Guillermo Federico ; Etcheverry, Mariano G.
    Background: Capsular contracture is the most frequent complication of breast implant augmentation. Although studies indicate that textured implants have a low incidence of contracture, they have been associated with anaplastic cell lymphoma, which influences the choice of surface. This study estimated and compared the annual capsular contracture rate of both smooth and textured implants in primary breast implants. Methods: Two hundred fifty-three patients (506 implants) were evaluated from January of 2017 to July of 2019; 42.2 percent of the implants were smooth and 57.8 percent were textured. The inframammary approach was used in the subfascial (55.3 percent) and submuscular (44.7 percent) pockets. The primary outcome was the appearance of capsular contracture (Baker grade II, III, and IV) within the first postoperative year. Results: Smooth implants had a higher capsular contracture rate at 1 year postoperatively compared with textured implants, although with borderline statistical significance (p = 0.06). Smooth surface breast implants in the subfascial plane had a 4-fold higher risk of contracture than those with a textured surface in the same plane (OR, 4.4; 95 percent confidence interval, 1.6 to 12.4). However, when placed in the submuscular plane, both textures had a similar contracture risk. The rate of contracture was similar after 2 years postoperatively (p = 0.21). Conclusions: Using the inframammary approach and a standardized technique, there were no significant differences in the incidence of capsular contracture between the smooth and textured implants. In the subfascial plane, the contracture rate with smooth implants was higher than with textured implants. However, in the submuscular plane, there was no difference between the surfaces. Clinical question/level of evidencw: Therapeutic, III.
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    Transmigration of Trypanosoma cruzi trypomastigotes through 3D cultures resembling a physiological environment
    (Wiley, 2020) Rodríguez, Matías Exequiel ; Rizzi, Mariana ; Caeiro, Lucas D. ; Masip, Yamil E. ; Perrone, Alina E ; Sánchez, Daniel O ; Bua, Jacqueline ; Tekiel, Valeria
    To disseminate and colonise tissues in the mammalian host, Trypanosoma cruzi trypomastogotes should cross several biological barriers. How this process occurs or its impact in the outcome of the disease is largely speculative. We examined the in vitro transmigration of trypomastigotes through three-dimensional cultures (spher oids) to understand the tissular dissemination of different T. cruzi strains. Virulent strains were highly invasive: trypomastigotes deeply transmigrate up to 50 µm inside spheroids and were evenly distributed at the spheroid surface. Parasites inside spher oids were systematically observed in the space between cells suggesting a para cellular route of transmigration. On the contrary, poorly virulent strains presented a weak migratory capacity and remained in the external layers of spheroids with a patch-like distribution pattern. The invasiveness—understood as the ability to trans migrate deep into spheroids—was not a transferable feature between strains, neither by soluble or secreted factors nor by co-cultivation of trypomastigotes from invasive and non-invasive strains. Besides, we demonstrated that T. cruzi isolates from chil dren that were born congenitally infected presented a highly migrant phenotype while an isolate from an infected mother (that never transmitted the infection to any of her children) presented significantly less migration. In brief, we demonstrated that in a 3D microenvironment each strain presents a characteristic migration pattern that can be associated to their in vivo behaviour. Altogether, data presented here repositionate spheroids as a valuable tool to study host–pathogen interactions.
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    Trypanosoma cruzi infection at the maternal-fetal interface : implications of parasite load in the congenital transmission and challenges in the diagnosis of infected newborns
    (Frontiers, 2019-6-7) Bustos, Patricia L. ; Milduberger, Natalia A. ; Volta, Viviana J. ; Perrone, Alina E ; Laucella, Susana A. ; Bua, Jacqueline
    Trypanosoma cruzi is the protozoan unicellular parasite that causes Chagas disease. It can be transmitted from infected mothers to their babies via the connatal route, thus being able to perpetuate even in the absence of Triatomine insect vectors. Chagas disease was originally endemic in Central and South America, but migration of infected women of childbearing age has spread the T. cruzi congenital infection to non-endemic areas like North America, Europe, Japan, and Australia. Currently, 7 million people are affected by this infection worldwide. This review focuses on the relevance of the T. cruzi parasite levels in different aspects of the congenital T. cruzi infection such as the mother-to-child transmission rate, the maternal and fetal immune response, and its impact on the diagnosis of infected newborns. Improvements in detection of this parasite, with tools that can be easily adapted to be used in remote rural areas, will make the early diagnosis of infected children possible, allowing a prompt trypanocidal treatment and avoiding the current loss of opportunities for the diagnosis of 100% of T. cruzi congenitally infected infants
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    Which thyroid nodules should be treated with surgery?
    (Jaypee Brothers Medical Publishers, 2021) Batallés, Stella Maris ; Novelli, Jorge Luis ; Brunàs, Oscar L. ; Brunás, Melisa E. ; Brunás, Anabela V.
    Aim: The objective of this work was to review the different conditions and characteristics of thyroid nodules that suggest surgical treatment. Background: A systematic literature searching was carried out in main databases (Medline, PubMed, EMBASE, LILACS, Google Academic, SciELO, and The Cochrane Library). The search was restricted to scientific papers published after 2005; only previous works that were inexcusable, specific references were included. The quality and consistency of the recommendations of treatment of thyroid nodules were systematically reviewed and assessed with the AGREE and AGREE-II guidelines. The different conditions and characteristics of thyroid nodules that suggest surgical treatment must be defined by valid, reliable, independent, and easily applied clinical-therapeutic guidelines. Several prestigious organizations from America, Europe, and Asia have developed guidelines containing recommendations for the surgical management of thyroid nodules. However, these recommendations may differ, and that could lead to confusion in many cases. Homogeneous guidelines are required to decide in which cases a thyroid nodule should be treated with a surgical intervention. Review results: Currently, fine needle aspiration under ultrasound guidance (FNA) has allowed cytological evaluation of non-palpable thyroid nodules from 2 mm in diameter. Nowadays, both ultrasound and FNA define–in most cases–whether or not a nodule requires surgery. Conclusion: Not all thyroid nodules require surgery. Surgical treatment is indicated in nodules with confirmed diagnosis or suspected malignancy, when the cytology of an FNA is undetermined, when goiter produces compressive symptoms, in cases of cervicothoracic goiters, recurrent cysts, or when the nodule grows during the follow-up. Clinical significance: To identify clinical and cytological characteristics in thyroid nodules to decide in which cases a thyroid nodule should be treated with surgery.