Artigos e Materiais de Revistas Científicas - LIM/29

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A coleção de Artigos e Materiais de Revistas Científicas engloba artigos originais, artigos de revisão, artigos de atualização, artigos técnicos, relatos de experiências, resenhas, ensaios, editoriais, cartas ao editor, debates, notas científicas e técnicas, depoimentos, entrevistas e pontos de vista. Consideram-se como artigos científicos originais os trabalhos redigidos para divulgação de informações e resultados sobre determinada pesquisa científica, publicados em periódico científico após avaliação por outros pesquisadores.

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WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease
(2022) FERRARI, M. T. M.; WATANABE, A.; SILVA, T. E. Da; GOMES, N. L.; BATISTA, R. L.; NISHI, M. Y.; PAULA, L. C. P. De; COSTA, E. C.; COSTA, E. M. F.; CUKIER, P.; ONUCHIC, L. F.; MENDONCA, B. B.; DOMENICE, S.
Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs∗14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.
ANCA-associated glomerulonephritis and lupus nephritis following COVID-19 vaccination: a case report and literature review
(2024) CAMPOS, Marcos Adriano Garcia; VALOIS, Tiago de Oliveira; MAGALHAES, Luis Eduardo; VASQUES, Lucas Fernandes; MEDEIROS, Rafael Goulart de; COSTA, Denise Maria do Nascimento; SALGADO FILHO, Natalino; NOGUEIRA, Raquel Moraes da Rocha; NEVES, Precil Diego Miranda de Menezes; SILVA, Gyl Eanes Barros
With the coverage of COVID-19 vaccination, it has been possible to observe the potential side effects of SARS-CoV-2 vaccines, with the most common ones being fever, myalgia, headache, and fatigue. However, an association has been observed between new and recurrent kidney injuries, mainly glomerulonephritis and lupus nephritis associated with ANCA, with the Pfizer-BioNTech, Moderna, Sinovac, and AstraZeneca vaccines, although the relationship between them is not clear. We report a case of ANCA-related vasculitis and lupus glomerulonephritis after the second dose of the AstraZeneca vaccine. The elderly patient presented significant worsening of kidney function after immunosuppression and complications after a new onset COVID-19 infection that led to death. We provide a literature review about kidney damage related to ANCA vasculitis after COVID-19 vaccine, aiming for a better understanding of the pathophysiological mechanism of kidney injury, its presentation, and treatment.
Effects of early exercise on cardiac function and lipid metabolism pathway in heart failure
(2023) SOUZA, Sergio Luiz Borges de; MOTA, Gustavo Augusto Ferreira; SILVA, Vitor Loureiro da; VILEIGAS, Danielle Fernandes; SANT'ANA, Paula Grippa; GREGOLIN, Cristina Schmitt; FIGUEIRA, Rebeca Lopes; BATAH, Sabrina Setembre; FABRO, Alexandre Todorovic; MURATA, Gilson Masahiro; BAZAN, Silmeia Garcia Zanati; OKOSHI, Marina Politi; CICOGNA, Antonio Carlos
We employed an early training exercise program, immediately after recovery from surgery, and before severe cardiac hypertrophy, to study the underlying mechanism involved with the amelioration of cardiac dysfunction in aortic stenosis (AS) rats. As ET induces angiogenesis and oxygen support, we aimed to verify the effect of exercise on myocardial lipid metabolism disturbance. Wistar rats were divided into Sham, trained Sham (ShamT), AS and trained AS (AST). The exercise consisted of 5-week sessions of treadmill running for 16 weeks. Statistical analysis was conducted by anova or Kruskal-Wallis test and Goodman test. A global correlation between variables was also performed using a two-tailed Pearson's correlation test. AST rats displayed a higher functional capacity and a lower cardiac remodelling and dysfunction when compared to AS, as well as the myocardial capillary rarefaction was prevented. Regarding metabolic properties, immunoblotting and enzymatic assay raised beneficial effects of exercise on fatty acid transport and oxidation pathways. The correlation assessment indicated a positive correlation between variables of angiogenesis and FA utilisation, as well as between metabolism and echocardiographic parameters. In conclusion, early exercise improves exercise tolerance and attenuates cardiac structural and functional remodelling. In parallel, exercise attenuated myocardial capillary and lipid metabolism derangement in rats with aortic stenosis-induced heart failure.
The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats
(2023) RODRIGUES, Eder Anderson; ROSA, Camila Moreno; CAMPOS, Dijon Henrique Salome; DAMATTO, Felipe Cesar; MURATA, Gilson Masahiro; SOUZA, Lidiane Moreira; PAGAN, Luana Urbano; GATTO, Mariana; BROSLER, Jessica Yumi; SOUZA, Hebreia Oliveira Almeida; MARTINS, Mario Machado; BASTOS, Luciana Machado; TANNI, Suzana Erico; OKOSHI, Katashi; OKOSHI, Marina Politi
BackgroundSodium-glucose cotransporter (SGLT)2 inhibitors have displayed beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, their effects in Type 1 DM have not been established.ObjectiveTo evaluate the influence of long-term treatment with SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, energy metabolism, and metabolomics in rats with Type 1 DM.MethodsMale Wistar rats were divided into groups: Control (C, n = 15); DM (n = 15); and DM treated with dapagliflozin (DM + DAPA, n = 15) for 30 weeks. DM was induced by streptozotocin. Dapagliflozin 5 mg/kg/day was added to chow. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn.ResultsDM + DAPA presented lower glycemia and higher body weight than DM. Echocardiogram showed DM with left atrium dilation and left ventricular (LV) hypertrophy, dilation, and systolic and diastolic dysfunction. In LV isolated papillary muscles, DM had reduced developed tension, +dT/dt and -dT/dt in basal condition and after inotropic stimulation. All functional changes were attenuated by dapagliflozin. Hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) activity was lower in DM than C, and PFK and PK activity higher in DM + DAPA than DM. Metabolomics revealed 21 and 5 metabolites positively regulated in DM vs. C and DM + DAPA vs. DM, respectively; 6 and 3 metabolites were negatively regulated in DM vs. C and DM + DAPA vs. DM, respectively. Five metabolites that participate in cell membrane ultrastructure were higher in DM than C. Metabolites levels of N-oleoyl glutamic acid, chlorocresol and N-oleoyl-L-serine were lower and phosphatidylethanolamine and ceramide higher in DM + DAPA than DM.ConclusionLong-term treatment with dapagliflozin attenuates cardiac remodeling, myocardial dysfunction, and contractile reserve impairment in Type 1 diabetic rats. The functional improvement is combined with restored pyruvate kinase and phosphofructokinase activity and attenuated metabolomics changes.
Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial
(2023) ROVIN, Brad H.; BARRATT, Jonathan; HEERSPINK, Hiddo J. L.; ALPERS, Charles E.; BIELER, Stewart; CHAE, Dong-Wan; DIVA, Ulysses A.; FLOEGE, Juergen; GESUALDO, Loreto; INRIG, Jula K.; KOHAN, Donald E.; KOMERS, Radko; KOOIENGA, Laura Ann; LAFAYETTE, Richard; MAES, Bart; MALECKI, Robert; MERCER, Alex; NORONHA, Irene L.; OH, Se Won; PEH, Chen Au; PRAGA, Manuel; PRECIADO, Priscila; RADHAKRISHNAN, Jai; RHEAULT, Michelle N.; ROTE, William E.; TANG, Sydney C. W.; TESAR, Vladimir; TRACHTMAN, Howard; TRIMARCHI, Hernan; TUMLIN, James A.; WONG, Muh Geot; PERKOVIC, Vlado
Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function , outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia , Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1 center dot 0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2 center dot 7 mL/min per 1 center dot 73 m2 per year versus -3 center dot 8 mL/min per 1 center dot 73 m2 per year (difference 1 center dot 1 mL/min per 1 center dot 73 m2 per year, 95% CI 0 center dot 1 to 2 center dot 1; p=0 center dot 037); total 2-year slope (day 1-week 110) was -2 center dot 9 mL/min per 1 center dot 73 m2 per year versus -3 center dot 9 mL/min per 1 center dot 73 m2 per year (difference 1 center dot 0 mL/min per 1 center dot 73 m2 per year, 95% CI -0 center dot 03 to 1 center dot 94; p=0 center dot 058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42 center dot 8%, 95% CI -49 center dot 8 to -35 center dot 0, with sparsentan versus -4 center dot 4%, -15 center dot 8 to 8 center dot 7, with irbesartan; geometric least-squares mean ratio 0 center dot 60, 95% CI 0 center dot 50 to 0 center dot 72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0 center dot 7, 95% CI 0 center dot 4 to 1 center dot 2). Treatment -emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.
Integrated control strategies for dengue, Zika, and Chikungunya virus infections
(2023) CORTES, Nelson; LIRA, Aline; PRATES-SYED, Wasim; SILVA, Jaqueline Dinis; VUITIKA, Larissa; CABRAL-MIRANDA, William; DURAES-CARVALHO, Ricardo; BALAN, Andrea; CABRAL-MARQUES, Otavio; CABRAL-MIRANDA, Gustavo
Arboviruses are a major threat to public health in tropical regions, encompassing over 534 distinct species, with 134 capable of causing diseases in humans. These viruses are transmitted through arthropod vectors that cause symptoms such as fever, headache, joint pains, and rash, in addition to more serious cases that can lead to death. Among the arboviruses, dengue virus stands out as the most prevalent, annually affecting approximately 16.2 million individuals solely in the Americas. Furthermore, the re-emergence of the Zika virus and the recurrent outbreaks of chikungunya in Africa, Asia, Europe, and the Americas, with one million cases reported annually, underscore the urgency of addressing this public health challenge. In this manuscript we discuss the epidemiology, viral structure, pathogenicity and integrated control strategies to combat arboviruses, and the most used tools, such as vaccines, monoclonal antibodies, treatment, etc., in addition to presenting future perspectives for the control of arboviruses. Currently, specific medications for treating arbovirus infections are lacking, and symptom management remains the primary approach. However, promising advancements have been made in certain treatments, such as Chloroquine, Niclosamide, and Isatin derivatives, which have demonstrated notable antiviral properties against these arboviruses in vitro and in vivo experiments. Additionally, various strategies within vector control approaches have shown significant promise in reducing arbovirus transmission rates. These encompass public education initiatives, targeted insecticide applications, and innovative approaches like manipulating mosquito bacterial symbionts, such as Wolbachia. In conclusion, combatting the global threat of arbovirus diseases needs a comprehensive approach integrating antiviral research, vaccination, and vector control. The continued efforts of research communities, alongside collaborative partnerships with public health authorities, are imperative to effectively address and mitigate the impact of these arboviral infections on public health worldwide.
Neuroimmunology of rabies: New insights into an ancient disease
(2023) BASTOS, Victor; PACHECO, Vinicius; RODRIGUES, Erika D. L.; MORAES, Cassia N. S.; NOBILE, Adriel L.; FONSECA, Dennyson Leandro M.; SOUZA, Kamilla B. S.; VALE, Fernando Y. N. do; FILGUEIRAS, Igor S.; SCHIMKE, Lena F.; GIIL, Lasse M.; MOLL, Guido; CABRAL-MIRANDA, Gustavo; OCHS, Hans D.; VASCONCELOS, Pedro F. da Costa; MELO, Guilherme D. de; BOURHY, Herve; CASSEB, Livia M. N.; CABRAL-MARQUES, Otavio
Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID-19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality.
A short-term high-sugar diet is an aggravating factor in experimental allergic contact dermatitis
(2023) COELHO, Leila F.; CASARO, Mateus B.; RIBEIRO, Willian R.; MENDES, Eduardo; MURATA, Gilson; XANDER, Patricia; LINO-DOS-SANTOS-FRANCO, Adriana; OLIVEIRA, Fernando A.; FERREIRA, Caroline M.
Allergic contact dermatitis (ACD) is an inflammatory skin reaction whose incidence has increased and has been associated with a dietary pattern rich in saturated fats and refined sugars. Considering the increased incidence of ACD and the lack of research about the influence of a short-term high-sugar diet on dermatitis, our aim is to improve understanding of the influence of a high-sugar diet on ACD. We introduced a diet rich in sugar fifteen days before inducing contact dermatitis with oxazolone, in mice, and maintained it until the end of the experiment, which lasted three weeks in total. The dermatitis model increased cholesterol and triglycerides in the liver, and the combination of diet and dermatitis increased weight and worsened liver cholesterol measurements. Furthermore, the high-sugar diet increased the production of IL-6, IFN-gamma and TNF alpha in the skin, which may be involved in the increase in epithelial skin thickness observed in experimental ACD.
Changes in Skeletal Muscle Protein Metabolism Signaling Induced by Glutamine Supplementation and Exercise
(2023) JR, Carlos Flores Rodrigues; MURATA, Gilson Masahiro; GERLINGER-ROMERO, Frederico; NACHBAR, Renato Tadeu; MARZUCA-NASSR, Gabriel Nasri; GORJAO, Renata; VITZEL, Kaio Fernando; HIRABARA, Sandro Massao; PITHON-CURI, Tania Cristina; CURI, Rui
Aim: To evaluate the effects of resistance exercise training (RET) and/or glutamine supplementation (GS) on signaling protein synthesis in adult rat skeletal muscles. Methods: The following groups were studied: (1) control, no exercise (C); (2) exercise, hypertrophy resistance exercise training protocol (T); (3) no exercise, supplemented with glutamine (G); and (4) exercise and supplemented with glutamine (GT). The rats performed hypertrophic training, climbing a vertical ladder with a height of 1.1 m at an 80 degrees incline relative to the horizontal with extra weights tied to their tails. The RET was performed three days a week for five weeks. Each training session consisted of six ladder climbs. The extra weight load was progressively increased for each animal during each training session. The G groups received daily L-glutamine by gavage (one g per kilogram of body weight per day) for five weeks. The C group received the same volume of water during the same period. The rats were euthanized, and the extensor digitorum longus (EDL) muscles from both hind limbs were removed and immediately weighed. Glutamine and glutamate concentrations were measured, and histological, signaling protein contents, and mRNA expression analyses were performed. Results: Supplementation with free L-glutamine increased the glutamine concentration in the EDL muscle in the C group. The glutamate concentration was augmented in the EDL muscles from T rats. The EDL muscle mass did not change, but a significant rise was reported in the cross-sectional area (CSA) of the fibers in the three experimental groups. The levels of the phosphorylated proteins (pAkt/Akt, pp70S6K/p70S6K, p4E-BP1/4E-BP1, and pS6/S6 ratios) were significantly increased in EDL muscles of G rats, and the activation of p4E-BP1 was present in T rats. The fiber CSAs of the EDL muscles in T, G, and GT rats were increased compared to the C group. These changes were accompanied by a reduction in the 26 proteasome activity of EDL muscles from T rats. Conclusion: Five weeks of GS and/or RET induced muscle hypertrophy, as indicated by the increased CSAs of the EDL muscle fibers. The increase in CSA was mediated via the upregulated phosphorylation of Akt, 4E-BP1, p70S6k, and S6 in G animals and 4E-BP1 in T animals. In the EDL muscles from T animals, a decrease in proteasome activity, favoring a further increase in the CSA of the muscle fibers, was reported.
Complexity of malaria transmission dynamics in the Brazilian Atlantic Forest
(2021) DUARTE, Ana Maria Ribeiro de Castro; FERNANDES, Licia Natal; SILVA, Fabiana Santos; SICCHI, Igor Lucoves; MUCCI, Luis Filipe; CURADO, Izilda; FERNANDES, Aristides; MEDEIROS-SOUSA, Antonio Ralph; CERETTI-JUNIOR, Walter; MARRELLI, Mauro Toledo; EVANGELISTA, Eduardo; TEIXEIRA, Renildo; SUMMA, Juliana Laurito; NARDI, Marcello Schiavo; GARNICA, Margoth Ramos; LOSS, Ana Carolina; BUERY, Julyana Cerqueira; CERUTT, Crispim; PACHECO, M. Andreina; ESCALANTE, Ananias A.; SALLUM, Maria Anice Mureb; LAPORTA, Gabriel Zorello
Plasmodium malariae and Plasmodium vivax are protozoan parasites that can cause malaria in humans. They are genetically indistinguishable from, respectively, Plasmodium brasilianum and Plasmodium simium, i.e. parasites infecting New World non-human primates in South America. In the tropical rainforests of the Brazilian Atlantic coast, it has long been hypothesized that P. brasilianum and P. simium in platyrrhine primates originated from P. malariae and P. vivax in humans. A recent hypothesis proposed the inclusion of Plasmodium falciparum into the transmission dynamics between humans and non-human primates in the Brazilian Atlantic tropical rainforest. Herein, we assess the occurrence of human malaria in simians and sylvatic anophelines using field-collected samples in the Capivari-Monos Environmental Protection Area from 2015 to 2017. We first tested simian blood and anopheline samples. Two simian (Aloutta) blood samples (18%, n = 11) showed Plasmodium cytb DNA sequences, one for P. vivax and another for P. malariae. From a total of 9,416 anopheline females, we found 17 pools positive for Plasmodium species with a 18S qPCR assay. Only three showed P. cytb DNA sequence, one for P. vivax and the others for rodent malaria species (similar to Plasmodium chabaudi and Plasmodium berghei). Based on these results, we tested 25 rodent liver samples for the presence of Plasmodium and obtained P. falciparum cytb DNA sequence in a rodent (Oligoryzomys sp.) liver. The findings of this study indicate complex malaria transmission dynamics composed by parallel spillover-spillback of human malaria parasites, i.e. P. malariae, P. vivax, and P. falciparum, in the Brazilian Atlantic forest.
Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling
(2023) MOLL, Guido; LUECHT, Christian; GYAMFI, Michael Adu; FONSECA, Dennyson L. M. da; WANG, Pinchao; ZHAO, Hongfan; GONG, Zexian; CHEN, Lei; ASHRAF, Muhamad Imtiaz; HEIDECKE, Harald; HACKEL, Alexander Maximilian; DRAGUN, Duska; BUDDE, Klemens; PENACK, Olaf; RIEMEKASTEN, Gabriela; CABRAL-MARQUES, Otavio; WITOWSKI, Janusz; CATAR, Rusan
Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-alpha) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-alpha secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-alpha synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-alpha gene transcription and TNF-alpha-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses.
COVID-19 Vaccination and Serological Profile of a Brazilian University Population
(2023) BARRETO, Marina dos Santos; SILVA, Beatriz Soares da; SANTOS, Ronaldy Santana; SILVA, Deise Maria Rego Rodrigues; SILVA, Eloia Emanuelly Dias; MOURA, Pedro Henrique Macedo; SOUZA, Jessiane Bispo de; SANTANA, Lucas Alves da Mota; FONSECA, Dennyson Leandro M.; FILGUEIRAS, Igor Salerno; GUIMARAES, Adriana Gibara; CABRAL-MARQUES, Otavio; SCHIMKE, Lena F.; BORGES, Lysandro Pinto
Background: COVID-19 led to the suspension academic activities worldwide, affecting millions of students and staff. Methods: In this study, we evaluated the presence of IgM and IgG anti-SARS-CoV-2 antibodies in an academic population during the return to classes after a one-year suspension. The study took place over five months at a Brazilian university and included 942 participants. Results: We found that most participants had reactive IgG and non-reactive IgM. All received at least one dose, and 940 received two or more doses, of different COVID-19 vaccines. We obtained a higher average of memory antibodies (IgG) in participants who received the CoronaVac/ChAdOx1 combination. IgG was consistently distributed for each vaccine group, but individuals who completed the vaccination schedule had higher levels. There were no differences between antibodies and gender, presence of symptoms, and previous COVID-19 infection, but older participants (>53 years) and contacts of infected individuals had higher IgM levels. Conclusion: This study makes significant contributions to the assessment of antibodies in the academic environment, allowing us to infer that most participants had memory immunity and low indications of recent infection when returning to face-to-face classes, as well as demonstrating the need to monitor immunity and update vaccinations.
Is it possible to contain COVID-19 in a female prison in Brazil? A pilot study
(2023) SILVA, Eloia Emanuelly Dias; JESUS, Pamela Chaves de; MOURA, Pedro Henrique Macedo; SILVA, DeiseMaria Rego Rodrigues da; SANTOS, Raquel Teles dos; MARQUES, Otavio Cabral-; SANTANA, Lucas Alves da Mota; BORGES, Lysandro Pinto
Interferome signature dynamics during the anti-dengue immune response: a systems biology characterization
(2023) USUDA, Julia Nakanishi; PLACA, Desiree Rodrigues; FONSECA, Dennyson Leandro M.; MARQUES, Alexandre H. C.; FILGUEIRAS, Igor Salerno; CHAVES, Victor Gabriel Bastos; ADRI, Anny Silva; TORRENTES-CARVALHO, Amanda; HIRATA, Mario Hiroyuki; FREIRE, Paula Paccielli; CATAR, Rusan; CABRAL-MIRANDA, Gustavo; SCHIMKE, Lena F.; MOLL, Guido; CABRAL-MARQUES, Otavio
Dengue virus (DENV) infection manifests as a febrile illness with three distinct phases: early acute, late acute, and convalescent. Dengue can result in clinical manifestations with different degrees of severity, dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Interferons (IFNs) are antiviral cytokines central to the anti-DENV immune response. Notably, the distinct global signature of type I, II, and III interferon-regulated genes (the interferome) remains uncharacterized in dengue patients to date. Therefore, we performed an in-depth cross-study for the integrative analysis of transcriptome data related to DENV infection. Our systems biology analysis shows that the anti-dengue immune response is characterized by the modulation of numerous interferon-regulated genes (IRGs) enriching, for instance, cytokine-mediated signaling (e.g., type I and II IFNs) and chemotaxis, which is then followed by a transcriptional wave of genes associated with cell cycle, also regulated by the IFN cascade. The adjunct analysis of disease stratification potential, followed by a transcriptional meta-analysis of the interferome, indicated genes such as IFI27, ISG15, and CYBRD1 as potential suitable biomarkers of disease severity. Thus, this study characterizes the landscape of the interferome signature in DENV infection, indicating that interferome dynamics are a crucial and central part of the anti-dengue immune response.
Can a Therapeutic Strategy for Hypotension Improve Cerebral Perfusion and Oxygenation in an Experimental Model of Hemorrhagic Shock and Severe Traumatic Brain Injury?
(2023) BALZI, Ana Paula de Carvalho Canela; OTSUKI, Denise Aya; ANDRADE, Lucia; PAIVA, Wellingson; SOUZA, Felipe Lima; AURELIANO, Luiz Guilherme Cernaglia; MALBOUISSON, Luiz Marcelo Sa
BackgroundRestoration of brain tissue perfusion is a determining factor in the neurological evolution of patients with traumatic brain injury (TBI) and hemorrhagic shock (HS). In a porcine model of HS without neurological damage, it was observed that the use of fluids or vasoactive drugs was effective in restoring brain perfusion; however, only terlipressin promoted restoration of cerebral oxygenation and lower expression of edema and apoptosis markers. It is unclear whether the use of vasopressor drugs is effective and beneficial during situations of TBI. The objective of this study is to compare the effects of resuscitation with saline solution and terlipressin on cerebral perfusion and oxygenation in a model of TBI and HS.MethodsThirty-two pigs weighing 20-30 kg were randomly allocated into four groups: control (no treatment), saline (60 ml/kg of 0.9% NaCl), terlipressin (2 mg of terlipressin), and saline plus terlipressin (20 ml/kg of 0.9% NaCl + 2 mg of terlipressin). Brain injury was induced by lateral fluid percussion, and HS was induced through pressure-controlled bleeding, aiming at a mean arterial pressure (MAP) of 40 mmHg. After 30 min of circulatory shock, resuscitation strategies were initiated according to the group. The systemic and cerebral hemodynamic and oxygenation parameters, lactate levels, and hemoglobin levels were evaluated. The data were subjected to analysis of variance for repeated measures. The significance level established for statistical analysis was p < 0.05.ResultsThe terlipressin and saline plus terlipressin groups showed an increase in MAP that lasted until the end of the experiment (p < 0.05). There was a notable increase in intracranial pressure in all groups after starting treatment for shock. Cerebral perfusion pressure and cerebral oximetry showed no improvement after hemodynamic recovery in any group. The groups that received saline at resuscitation had the lowest hemoglobin concentrations after treatment.ConclusionsThe treatment of hypotension in HS with saline and/or terlipressin cannot restore cerebral perfusion or oxygenation in experimental models of HS and severe TBI. Elevated MAP raises intracranial pressure owing to brain autoregulation dysfunction caused by TBI.
Bartter Syndrome-Related Variants Distribution: Brazilian Data and Its Comparison with Worldwide Cohorts
(2023) VAISBICH, Maria Helena; MESSA, Ana Carola Hebbia Lobo; RANGEL-SANTOS, Andreia Cristiane; FERREIRA, Juliana Caires de Oliveira Achili; NUNES, Fernanda Andrade Macaferri da Fonseca; WATANABE, Andreia
Background: Genetic testing is recommended for accurate diagnosis of Bartter syndrome (BS) and serves as a basis for implementing specific target therapies. However, populations other than Europeans and North Americans are underrepresented in most databases and there are uncertainties in the genotype-phenotype correlation. We studied Brazilian BS patients, an admixed population with diverse ancestry. Methods: We evaluated the clinical and mutational profile of this cohort and performed a systematic review of BS mutations from worldwide cohorts. Results: Twenty-two patients were included; Gitelman syndrome was diagnosed in 2 siblings with antenatal BS and congenital chloride diarrhea in 1 girl. BS was confirmed in 19 patients: BS type 1 in 1 boy (antenatal BS); BS type 4a in 1 girl and BS type 4b in 1 girl, both of them with antenatal BS and neurosensorial deafness; BS type 3 (CLCNKB mutations): 16 cases. The deletion of the entire CLCNKB (1-20 del) was the most frequent variant. Patients carrying the 1-20 del presented earlier manifestations than those with other CLCNKB-mutations and the presence of homozygous 1-20 del was correlated with progressive chronic kidney disease. The prevalence of the 1-20 del in this BS Brazilian cohort was similar to that of Chinese cohorts and individuals of African and Middle Eastern descent from other cohorts. Conclusion: This study expands the genetic spectrum of BS patients with different ethnics, reveals some genotype/phenotype correlations, compares the findings with other cohorts, and provides a systematic review of the literature on the distribution of BS-related variants worldwide.
Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach
(2023) FONSECA, Dennyson Leandro M.; FILGUEIRAS, Igor Salerno; MARQUES, Alexandre H. C.; VOJDANI, Elroy; HALPERT, Gilad; OSTRINSKI, Yuri; BAIOCCHI, Gabriela Crispim; PLACA, Desiree Rodrigues; FREIRE, Paula P.; POUR, Shahab Zaki; MOLL, Guido; CATAR, Rusan; LAVI, Yael Bublil; SILVERBERG, Jonathan I.; ZIMMERMAN, Jason; CABRAL-MIRANDA, Gustavo; CARVALHO, Robson F.; KHAN, Taj Ali; HEIDECKE, Harald; DALMOLIN, Rodrigo J. S.; LUCHESSI, Andre Ducati; OCHS, Hans D.; SCHIMKE, Lena F.; AMITAL, Howard; RIEMEKASTEN, Gabriela; ZYSKIND, Israel; ROSENBERG, Avi Z.; VOJDANI, Aristo; SHOENFELD, Yehuda; CABRAL-MARQUES, Otavio
Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid ss peptide, ss catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients >= 50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes.
Cardiac structural and functional findings in Persian cats with autosomal dominant polycystic kidney disease
(2020) GUERRA, Juliana Mariotti; PELLEGRINO, Arine; DANIEL, Alexandre Goncalves Teixeira; FREITAS, Mariana Ferreira de; CARDOSO, Natalia Cavalca; PESSOA, Rebecca Bastos; LUCCA, Gabriel Garone de; LARSSON, Maria Helena Matiko Akao; ONUCHIC, Luiz Fernando; QUEIROGA, Felisbina Luisa; COGLIATI, Bruno
Autosomal dominant polycystic kidney disease (ADPKD) has been related to left ventricular structural and functional abnormalities in human patients. The present study aimed to evaluate the cardiac structural and functional findings in Persian cats with ADPKD. Client-owned ADPKD (n=12) and non-ADPKD (n 12) Persian cats were enrolled in this study. The animals underwent echo- and electrocardiographic (ECG) examinations, and non-invasive measurements of systolic blood pressure (SBP) were obtained. Both groups were similar regarding hematological and biochemical parameters, including white blood cell count and levels of blood urea nitrogen, creatinine, total protein and thyroxine. There were no differences related to ECG parameters between ADPKD and non-ADPKD cats. Left ventricular hypertrophy (LVH) was demonstrated in 6/12 (50%) normotensive ADPKD cats with preserved renal function. There were no differences between animal groups regarding the echocardiographic parameters, including left ventricular ejection fraction and shortening fraction; however, basal interventricular septal thickness at end-diastole near the left ventricular outflow tract and aortic artery flow velocity showed slightly elevated values in ADPKD-cats. Our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients; however, large-scale cohort studies are necessary to distinguish the possibilities of a true linkage between ventricular myocardial hypertrophy and ADPKD in this breed.
Rare genetic variants involved in multisystem inflammatory syndrome in children: a multicenter Brazilian cohort study
(2023) REIS, Barbara Carvalho Santos Dos; FACCION, Roberta Soares; CARVALHO, Flavia Amendola Anisio de; MOORE, Daniella Campelo Batalha Cox; ZUMA, Maria Celia Chaves; PLACA, Desiree Rodrigues; FILGUEIRAS, Igor Salerno; FONSECA, Dennyson Leandro Mathias; CABRAL-MARQUES, Otavio; BONOMO, Adriana Cesar; SAVINO, Wilson; FREITAS, Flavia Cristina de Paula; FAORO, Helisson; PASSETTI, Fabio; ROBAINA, Jaqueline Rodrigues; OLIVEIRA, Felipe Rezende Caino de; BELLINAT, Ana Paula Novaes; ZEITEL, Raquel de Seixas; SALU, Margarida dos Santos; OLIVEIRA, Mariana Barros Genuino de; RODRIGUES-SANTOS, Gustavo; PRATA-BARBOSA, Arnaldo; VASCONCELOS, Zilton Farias Meira de
IntroductionDespite the existing data on the Multisystem Inflammatory Syndrome in Children (MIS-C), the factors that determine these patients evolution remain elusive. Answers may lie, at least in part, in genetics. It is currently under investigation that MIS-C patients may have an underlying innate error of immunity (IEI), whether of monogenic, digenic, or even oligogenic origin. MethodsTo further investigate this hypothesis, 30 patients with MIS-C were submitted to whole exome sequencing. ResultsAnalyses of genes associated with MIS-C, MIS-A, severe covid-19, and Kawasaki disease identified twenty-nine patients with rare potentially damaging variants (50 variants were identified in 38 different genes), including those previously described in IFNA21 and IFIH1 genes, new variants in genes previously described in MIS-C patients (KMT2D, CFB, and PRF1), and variants in genes newly associated to MIS-C such as APOL1, TNFRSF13B, and G6PD. In addition, gene ontology enrichment pointed to the involvement of thirteen major pathways, including complement system, hematopoiesis, immune system development, and type II interferon signaling, that were not yet reported in MIS-C. DiscussionThese data strongly indicate that different gene families may favor MIS- C development. Larger cohort studies with healthy controls and other omics approaches, such as proteomics and RNAseq, will be precious to better understanding the disease dynamics.
Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery
(2023) COUTO, Pedro S.; AL-ARAWE, Nada; FILGUEIRAS, Igor S.; FONSECA, Dennyson L. M.; HINTERSEHER, Irene; CATAR, Rusan A.; CHINNADURAI, Raghavan; BERSENEV, Alexey; CABRAL-MARQUES, Otavio; MOLL, Guido; VERTER, Frances
During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection.

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