Publications by authors named "Fernando Costa"

515 Publications

Nonsurgical periodontal therapy decreases the severity of rheumatoid arthritis and the plasmatic and salivary levels of RANKL and Survivin: a short-term clinical study.

Clin Oral Investig 2021 May 5. Epub 2021 May 5.

Department of Dental Clinics, Oral Pathology, and Oral Surgery, School of Dentistry, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.

Aim: To investigate the influence of nonsurgical periodontal treatment (NSPT) on clinical periodontal status, rheumatoid arthritis (RA) activity, and plasmatic and salivary levels of biomarkers through a controlled clinical trial on individuals with RA and periodontitis (PE).

Methods: Sixty-six individuals from a convenience sample were considered eligible and consecutively allocated in 3 groups: (1) individuals without PE and RA (-PE-RA, n = 19); (2) individuals without PE and with RA (-PE+RA, n = 23), and (3) individuals with PE and RA (+PE+RA, n = 24). Full-mouth periodontal clinical examinations, Disease Activity Score (DAS-28) evaluations, and analysis in plasma and saliva of RANKL, OPG, RANKL/OPG, and Survivin were performed at baseline (T1) and 45 days after NSPT (T2).

Results: NSPT in the +PE+RA group was very effective to improve periodontal condition. At T2, significant reductions in DAS-28 were observed in +PE+RA (p = 0.011). Significantly higher levels of Survivin and RANKL were observed in saliva and plasma from RA individuals (with and without PE) compared to controls. Additionally, Survivin e RANKL demonstrated positive correlations with DAS-28 and an expressively significant reduction in +PE+RA at T2 (p < 0.001).

Conclusions: NSPT was effective on improving both the periodontal and the RA clinical status and reducing the concentration of Survivin and RANKL in saliva and plasma.

Practical Implications: Nonsurgical periodontal treatment was effective on reducing the concentration of Survivin and RANKL and on improving both the periodontal and the RA clinical status of affected individuals.

Trial Registration: Brazilian Registry of Clinical Trials (ReBEC) protocol #RBR-8g2bc8 ( http://www.ensaiosclinicos.gov.br/rg/RBR-8g2bc8/ ).
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http://dx.doi.org/10.1007/s00784-021-03950-4DOI Listing
May 2021

Chitosan-based biomaterial and hyaluronic acid on the repair of intrabuccal bone defects in rats.

J Int Acad Periodontol 2021 Apr;23(2):138-149

Pontifical Catholic University of Minas Gerais, Belo Horizonte, Brazil.

Aims: This experimental study aimed to evaluate the effects of a three-dimensional matrix of chitosan-gelatin (CG) associated with 1% hyaluronic acid (HA) on gingival healing and repairing of intrabuccal bone defects in rats.

Materials And Methods: Standardized bone defects were created in the region of the upper 1st molars of rats. Study groups were created according to bone defects (n=6/group) treatment: Control group (CO); blood clot; HA group; CG group, and HA+CG group. After 7 and 21 days, the animals were sacrificed for histological and histomorphometric analysis. Bone formation was quantified as the percentage of newly synthesized collagen, visualized by Gomori's trichromic. Clinical/macroscopic evaluation was based on predetermined scores of gingival healing.

Results: Treatment with HA improved gingival healing at day 7, but no statistical differences were found among groups at day 21. The morphometric analysis demonstrated better results after the treatment of bone defects with both HA and CG on day 21. The three-dimensional structure of CG prevented the invasion of epithelial tissue into the defect, preserving its original volume.

Conclusions: Isolated use of a chitosan-gelatin osteoconductive matrix promoted greater bone deposition and preserved the volume of the surgical site, irrespective of the presence of hyaluronic acid.
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April 2021

Effect of the Andean Geography and Climate on the Specialized Metabolism of Its Vegetation: The Subtribe Espeletiinae (Asteraceae) as a Case Example.

Metabolites 2021 Apr 4;11(4). Epub 2021 Apr 4.

AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto SP 14040-903, Brazil.

The Andean mountains are 'center stage' to some of the most spectacular examples of plant diversifications, where geographic isolation and past climatic fluctuations have played a major role. However, the influence of Andean geography and climate as drivers of metabolic variation in Andean plants is poorly elucidated. Here, we studied the influence of those factors on the metabolome of the subtribe Espeletiinae (Asteraceae) using liquid chromatography coupled to high-resolution mass spectrometry data of over two hundred samples from multiple locations. Our results demonstrate that metabolic profiles can discriminate Espeletiinae taxa at different geographic scales, revealing inter- and intraspecific metabolic variations: at the country level, segregation between Colombian and Venezuelan taxa was observed; regionally, between páramo massifs; and locally, between páramo complexes. Metabolic differences in Espeletiinae were mainly explained by geographic isolation, although differences in taxonomic genera, temperature, and elevation, were also important. Furthermore, we found that different species inhabiting the same páramo complex showed stronger chemical similarities than the same species at different locations, corroborating that geographic isolation represents the main driver of metabolic change in Espeletiinae. The current study serves as a starting point to fill in the gaps in how Andean geography and climate have shaped the metabolism of its vegetation and reveal the potential of untargeted metabolomics to study the environmental physiology of plants.
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http://dx.doi.org/10.3390/metabo11040220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065660PMC
April 2021

Are neutrophil extracellular traps the link for the cross-talk between periodontitis and rheumatoid arthritis physiopathology?

Rheumatology (Oxford) 2021 Mar 22. Epub 2021 Mar 22.

Department of Oral Surgery and Pathology, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.

Objectives: Neutrophil extracellular traps (NETs) play a role in the pathogenesis of periodontitis and rheumatoid arthritis (RA). However, it remains poorly understood whether NETs participate in the cross-talk between periodontitis and RA. Herein, we investigated the production of NETs in individuals with periodontitis and RA and its association with clinical parameters. The impact of periodontal therapy on RA and NET release was also assessed.

Methods: The concentration of NETs and cytokines was determined in the saliva and plasma of individuals with early RA (n = 24), established RA (n = 64), and individuals without RA (n = 76). The influence of periodontitis on the production of NETs and cytokines was also evaluated.

Results: Individuals with early RA had a higher concentration of NETs in saliva and plasma than individuals with established RA or without RA. Periodontitis resulted in an increase in the concentration of NETs of groups of individuals without RA and with early RA. The proportion of individuals with high concentrations of IL-6, IL-10 and GM-CSF was higher among individuals with periodontitis than among individuals without periodontitis. The concentrations of TNF-α, IL-6, IL-17/IL-25, and IL-28A were particularly high in individuals with early RA. Worse periodontal clinical parameters, RA onset and RA activity were significantly associated with circulating NETs. Periodontal therapy was associated with a reduction in the concentration of NETs and inflammatory cytokines and amelioration in periodontitis and RA.

Conclusion: This study reveals that NETs are a possible link between periodontitis and RA, with periodontal therapy resulting in a dramatic switch in circulating NET levels.
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http://dx.doi.org/10.1093/rheumatology/keab289DOI Listing
March 2021

First report on the DC. Essential oil and identification of potential biological targets of its major compounds.

Nat Prod Res 2021 Mar 7:1-4. Epub 2021 Mar 7.

Program of Post-Graduation in Chemistry, Federal University of Pará, Belém, Brazil.

In the present study, the essential oil (EO) of DC. or was extracted by hydrodistillation, and the identification and quantification of volatile compounds were performed by GC-MS and GC-FID. leaves were collected from the Magalhães Barata, northeast of the State of Pará (Brazil) in March and September of 2019. Moreover, we used computational approaches to evaluate possible biological targets for the major compounds of the EO. In the sample obtained in March, 50 compounds were identified, with hydrocarbon sesquiterpenes being the predominant ones with the content of 80.52%. In the sample collected in September, 58 compounds were identified, and the chemical class of hydrocarbon monoterpenes and sesquiterpenes were the dominant ones with contents of 43.36 and 31.29%, respectively. Computational methods demonstrated that some major compounds have potential biological activity against some strains of pathogenic bacteria, as well as against molecular targets involved in cancer development.
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http://dx.doi.org/10.1080/14786419.2021.1893724DOI Listing
March 2021

Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease.

Front Immunol 2020 4;11:617962. Epub 2021 Feb 4.

Hematology and Hemotherapy Center, University of Campinas, UNICAMP, Campinas, Brazil.

Sickle cell disease (SCD), one of the most common hemoglobinopathies worldwide, is characterized by a chronic inflammatory component, with systemic release of inflammatory cytokines, due to hemolysis and vaso-occlusive processes. Patients with SCD demonstrate dysfunctional T and B lymphocyte responses, and they are more susceptible to infection. Although dendritic cells (DCs) are the main component responsible for activating and polarizing lymphocytic function, and are able to produce pro-inflammatory cytokines found in the serum of patients with SCD, minimal studies have thus far been devoted to these cells. In the present study, we identified the subpopulations of circulating DCs in patients with SCD, and found that the bloodstream of the patients showed higher numbers and percentages of DCs than that of healthy individuals. Among all the main DCs subsets, inflammatory DCs (CD14 DCs) were responsible for this rise and correlated with higher reticulocyte count. The patients had more activated monocyte-derived DCs (mo-DCs), which produced MCP-1, IL-6, and IL-8 in culture. We found that a CD14 mo-DC subset present in culture from some of the patients was the more activated subset and was mainly responsible for cytokine production, and this subset was also responsible for IL-17 production in co-culture with T lymphocytes. Finally, we suggest an involvement of heme oxygenase in the upregulation of CD14 in mo-DCs from the patients, indicating a potential mechanism for inducing inflammatory DC differentiation from circulating monocytes in the patients, which correlated with inflammatory cytokine production, T lymphocyte response skewing, and reticulocyte count.
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http://dx.doi.org/10.3389/fimmu.2020.617962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890087PMC
February 2021

Alpha thalassemia, but not β-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort.

Ann Hematol 2021 Apr 13;100(4):921-931. Epub 2021 Feb 13.

Genetics Postgraduate Program, Centre of Biosciences, Federal University of Pernambuco, Recife, Brazil.

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.
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http://dx.doi.org/10.1007/s00277-021-04450-xDOI Listing
April 2021

Neutrophil extracellular trap regulators in sickle cell disease: Modulation of gene expression of PADI4, neutrophil elastase, and myeloperoxidase during vaso-occlusive crisis.

Res Pract Thromb Haemost 2021 Jan 16;5(1):204-210. Epub 2020 Dec 16.

School of Medical Sciences University of Campinas Campinas Brazil.

Background: Recent evidence suggests that generation of neutrophil extracellular traps (NETosis), one of the components of immunothrombosis, is associated with the pathogenesis of both venous thromboembolism and sickle cell disease (SCD). NETosis is a complex process regulated by several proteins such as peptidyl arginine deaminase 4 (PADI4), neutrophil elastase (ELANE), and myeloperoxidase (MPO). Among these regulators, PADI4 is responsible of histone citrullination, an essential step for NETosis. Accordingly, its inhibition has been recently cited as a promising therapeutic strategy for diseases such as SCD. Although attractive, this strategy requires supportive evidence of its role in the pathogenesis of SCD.

Patients And Methods: Patients from two independent cohorts were enrolled in this study. Samples were obtained at steady state (53 patients) or during acute episodes of vaso-occlusive crisis (VOC; 28 patients) in patients from cohort 1. mRNA was extracted from granulocytes to analyze , , and  expression by qPCR. Furthermore, plasma activity of PADI4 was assessed from an independent cohort in 15 patients, within 24 hours from admission for VOC. Race-matched healthy individuals from the same geographic regions were used as controls for each cohort.

Results And Conclusions: Higher levels of gene expression of  and  were observed during VOC. Furthermore, plasma activity of PADI4 was higher in acute VOC when compared to healthy individuals. These results demonstrate that NETosis regulators are modulated during acute VOC, and pave the way for studies of  inhibition as a therapeutic strategy for acute VOC in SCD.
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http://dx.doi.org/10.1002/rth2.12463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845058PMC
January 2021

Influence of UGT1A1 promoter polymorphism, α-thalassemia and β haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort.

Ann Hematol 2021 Apr 1;100(4):903-911. Epub 2021 Feb 1.

Genetics Postgraduate Program, Federal University of Pernambuco, Recife, Brazil.

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and β haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and β haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with β haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.
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http://dx.doi.org/10.1007/s00277-021-04422-1DOI Listing
April 2021

The Effects of Patient Compliance in Supportive Periodontal Therapy on Tooth Loss: A systematic Review and Meta-analysis.

J Int Acad Periodontol 2021 01 1;23(1):17-30. Epub 2021 Jan 1.

Department of Dentistry, Periodontics Research Division, University of Taubaté, Taubaté, São Paulo, Brazil.

Background: The present review aimed to assess the impact of being a complier to supportive periodontal therapy (SPT), when compared to not being a complier, on tooth loss in patients with periodontitis.

Methods: Prospective and retrospective observational studies were included. MEDLINE, EMBASE, and LILACS databases were searched up to May 2019. The odds-ratio (OR) and standard error (SE) values of the studied groups (compliant or non-compliant) were converted to logOR, and the results of individual studies were grouped using a random effects model.

Results: From a total of 1815 articles initially searched, 13 retrospective studies and one prospective study comparing tooth loss of complier and non-complier individuals in SPT were included. Meta-analysis of eight studies showed that non-compliers in SPT have an increased risk of tooth loss when compared with compliers. Overall meta-analysis demonstrated that non-compliant patients in SPT have a 26% increased risk of tooth loss when compared with compliant patients (OR = 1.26; 95% CI = 1.06 to 1.51, Heterogeneity: I2 = 0%, p = 0.008).

Conclusions: Patients with periodontitis who do not comply in SPT have a higher risk of tooth loss than compliant patients. Oral health professionals should implement measures to obtain optimal adherence by patients in SPT.
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January 2021

Evaluation of polymorphisms and the risk for age-related macular degeneration in a Southeastern Brazilian population.

Exp Biol Med (Maywood) 2021 Jan 19:1535370220985466. Epub 2021 Jan 19.

Laboratory of Human Genetics, Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas, Campinas, SP 13083-875, Brazil.

This study aimed to evaluate the role of polymorphisms (rs429358 and rs7412) in the risk of age-related macular degeneration in a sample of the Southeastern Brazilian population. Seven hundred and five unrelated individuals were analyzed, 334 with age-related macular degeneration (case group), and 371 without the disease (control group). In the case group, patients were further stratified according to disease phenotypes, divided into dry and wet age-related macular degeneration, and non-advanced and advanced age-related macular degeneration. polymorphisms (rs429358 and rs7412) were evaluated through polymerase chain reaction and direct sequencing. In the comparison of cases vs. controls, none of the associations reached statistical significance, considering the Bonferroni-adjusted -value, although there was a suggestive protection for the E3/E4 genotype (OR = 0.626; -value = 0.037) and E4 carriers (OR = 0.6515; -value = 0.047). Statistically significant protection for both the E3/E4 genotype and E4 carriers was observed in the comparisons: advanced age-related macular degeneration vs. controls (OR = 0.3665, -value = 0.491 × 10 and OR = 0.4031, -value = 0.814 × 10, respectively), advanced age-related macular degeneration vs. non-advanced age-related macular degeneration (OR = 0.2529, -value = 0.659 × 10 and OR = 0.2692, -value = 0.631 × 10, respectively). In the comparison of wet age-related macular degeneration vs. control, protection was statistically significant only for E3/E4 (OR = 0.4052, -value = 0.001). None of the comparisons demonstrated any significant association for E2 genotypes or E2 carriers in age-related macular degeneration risk in this study. Findings suggest a protective role of the E4 haplotype in the gene in the risk for advanced and wet forms of age-related macular degeneration, in a sample of the Brazilian population. To our knowledge, this is the first Brazilian study to show the association between polymorphisms and age-related macular degeneration.
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http://dx.doi.org/10.1177/1535370220985466DOI Listing
January 2021

Screening for myeloid mutations in patients with myelodysplastic syndromes and AML with myelodysplasia-related changes.

Hematol Transfus Cell Ther 2021 Jan 3. Epub 2021 Jan 3.

Federal University of Pernambuco, Recife, PE, Brazil.

Introduction: One of the most critical complications in myelodysplastic syndromes (MDS) is the progression to acute myeloid leukemia (AML). The dynamics of clonal evolution in MDS and how acquired mutations can be used as biomarkers to track disease progression remains under investigation.

Objective And Method: Herein, we investigated the frequency of common myeloid clonal mutations (FLT3, NPM1, JAK2, IDH1 and IDH2) in 88 patients with MDS and 35 AML patients with myelodysplasia-related changes, followed at a single reference center in northeastern Brazil.

Results: Overall, 9/88 (10%) of the MDS patients and 9/35 (26%) of the secondary AML patients had at least one mutation. While the JAK2 V617F mutation was the most frequent in the MDS patients, the FLT3, NPM1, IDH1 and IDH2 mutations were more frequently found in the secondary AML group. Furthermore, there was a higher frequency of FLT3, NPM1, IDH1 and IDH2 mutations in MDS patients classified as high-risk subtypes than in those of lower risk.

Conclusion: Despite the limited sample size, our data suggest that mutations in FLT3, NPM1, IDH1 and IDH2 genes could be potential biomarkers to detect early disease progression in MDS.
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http://dx.doi.org/10.1016/j.htct.2020.10.967DOI Listing
January 2021

Endothelial Barrier Integrity Is Disrupted by Heme and by Serum From Sickle Cell Disease Patients.

Front Immunol 2020 14;11:535147. Epub 2020 Dec 14.

School of Medical Sciences, University of Campinas, Campinas, Brazil.

Free extracellular heme has been shown to activate several compartments of innate immunity, acting as a danger-associated molecular pattern (DAMP) in hemolytic diseases. Although localized endothelial barrier (EB) disruption is an important part of inflammation that allows circulating leukocytes to reach inflamed tissues, non-localized/deregulated disruption of the EB can lead to widespread microvascular hyperpermeability and secondary tissue damage. In mouse models of sickle cell disease (SCD), EB disruption has been associated with the development of a form of acute lung injury that closely resembles acute chest syndrome (ACS), and that can be elicited by acute heme infusion. Here we explored the effect of heme on EB integrity using human endothelial cell monolayers, in experimental conditions that include elements that more closely resemble conditions. EB integrity was assessed by electric cell-substrate impedance sensing in the presence of varying concentrations of heme and sera from SCD patients or healthy volunteers. Heme caused a dose-dependent decrease of the electrical resistance of cell monolayers, consistent with EB disruption, which was confirmed by staining of junction protein VE-cadherin. In addition, sera from SCD patients, but not from healthy volunteers, were also capable to induce EB disruption. Interestingly, these effects were not associated with total heme levels in serum. However, when heme was added to sera from SCD patients, but not from healthy volunteers, EB disruption could be elicited, and this effect was associated with hemopexin serum levels. Together our studies provide additional support to the concept of heme as a DAMP in hemolytic conditions.
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http://dx.doi.org/10.3389/fimmu.2020.535147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767881PMC
April 2021

Low-load resistance training with blood flow restriction prevent renal function decline: The role of the redox balance, angiotensin 1-7 and vasopressin.

Physiol Behav 2021 Mar 16;230:113295. Epub 2020 Dec 16.

Post-Graduate Program of Physical Education of Catholic University of Brasilia, Federal District, Brazil-71966-700. Electronic address:

Aims: We sought to investigate the effect of resistance training (RT) and low-load RT with moderate blood flow restriction (RT+BFR) on blood pressure, exercise pressor response, redox balance and vasoactive peptides, body composition and muscle strength in patients with stage two of chronic kidney disease (CKD).

Methods: We conducted a 6-month randomized controlled exercise intervention in 90 male and female hypertensive CKD patients (58±9 years with estimated glomerular filtration rate (eGFR; of 66.1 ± 1.2 mL/kg/1.73m). Participants were randomized to one of three groups (n = 30/group); control group (CTL), RT, and RT+BFR. RT and RT+BFR performed three weekly training sessions using similar periodization for six months (two-month mesocycles), but of different intensities.

Results: There was similarly effects between RT and RT+BFR in reducing systolic and diastolic blood pressure during daytime and 24hour period (RT: 10.4%; RT+BFR: 10.3% of decrease), fat mass, F-isoprostanes, asymmetric dimethylarginine (ADMA) and vasopressin (p<0.05 pre-vs post). Also promoted the increase of angiotensin 1-7, nitric oxide (NO), catalase, Trolox equivalent and muscle strength (p<0.05). Both training models attenuated the decline of estimated glomerular filtration rate (p<0.0001 vs CTL). However, only RT+BFR was associated with lower discomfort during exercise (p<0.0001 pre-vs post). Statistical significance was considered with p < 0.05.

Conclusion: These findings suggest low-load RT+BFR as a promising non-pharmacological strategy to control blood pressure, oxidative stress, vasoactive peptides, and consequently, attenuate the decrease of the eGFR.
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http://dx.doi.org/10.1016/j.physbeh.2020.113295DOI Listing
March 2021

Non-biological Complex Drugs (NBCDs): Complex Pharmaceuticals in Need of Individual Robust Clinical Assessment Before Any Therapeutic Equivalence Decision.

Front Med (Lausanne) 2020 23;7:590527. Epub 2020 Nov 23.

Unidade de Farmacologia Clínica, Centro Hospitalar Universitário de S. João, Porto, Portugal.

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs "follow-on products" approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of "well-established use" applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.
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http://dx.doi.org/10.3389/fmed.2020.590527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719831PMC
November 2020

Correction to: Clinical and microbiological effects of non-surgical periodontal treatment in individuals with rheumatoid arthritis: a controlled clinical trial.

Odontology 2021 Apr;109(2):494-495

Department of Dental Clinics, Oral Pathology, and Oral Surgery, Department of Periodontology, Faculty of Dentistry, Federal University of Minas Gerais, Antônio Carlos Avenue, 6627, Pampulha, PO Box 359, Belo Horizonte, Minas Gerais, 31270-901, Brazil.

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http://dx.doi.org/10.1007/s10266-020-00579-9DOI Listing
April 2021

"Association of gene polymorphisms with primary open angle glaucoma in Brazilian patients".

Ophthalmic Genet 2021 02 7;42(1):53-61. Epub 2020 Dec 7.

Department of Ophthalmology, Faculty of Medical Sciences, University of Campinas - UNICAMP , Campinas, Brazil.

: Primary open-angle glaucoma (POAG) is a multifactorial disease that affects 65.5 million people worldwide. In addition to the genetic variants already established as indicators of greater risk for POAG, the apolipoprotein () gene has been studied in some populations, with controversial results. The aim of this study is to investigate the frequency of the genetic variants of in the Brazilian population, and to evaluate the association between these polymorphisms and the risk of POAG. : variants (rs429358; rs7412) were genotyped in 402 POAG patients and 401 controls. We evaluated the association between genetic variants and the risk for POAG, as well as the correlation between the requirement of glaucoma surgery and the polymorphisms. : Among the three gene isoforms, we found a low frequency of alleles ε2 (7.34%) and ε4 (11.76%), but a high frequency of ε3 (80.88%) in our population. When compared to ε3ε3 reference genotype, ε2 allele-carriers (OR = 1.516; -value = 0.04) and ε2ε3 genotype (OR = 1.655; -value = 0.02) were associated with a greater risk for POAG. An additive genetic model confirmed the influence of the ε2 allele in the risk of POAG in this sample of the Brazilian population (OR = 1.502; -value = 0.04). There was no significant association between the analyzed genotypes and the requirement or number of glaucoma surgeries ( > .05). : Brazilian individuals carrying the ε2 allele may be at an increased risk for the development of POAG.
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http://dx.doi.org/10.1080/13816810.2020.1849314DOI Listing
February 2021

Effect of compliance during periodontal maintenance therapy on c-reactive protein levels: a 6-year follow-up.

J Clin Periodontol 2021 03 23;48(3):400-409. Epub 2020 Dec 23.

School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Aims: To longitudinally evaluate the effects of compliance during periodontal maintenance therapy (PMT) on C-reactive protein (CRP) levels and its relation to periodontal status.

Materials And Methods: A subsample comprising of 30 matched pairs was taken from a previous 6-year longitudinal study under PMT. Pairs were composed of one regular (RC) and one irregular (IC) compliers, matched by age and sex. Periodontal parameters and plasma samples were collected at 3 times: T1[prior to active periodontal therapy (APT)], T2(after APT), and T3(after 6 years). CRP plasma levels were quantified using ELISA.

Results: RC presented better clinical periodontal status, lower recurrence of periodontitis (sites with PD ≥4 mm and CAL ≥3 mm, together with the persistence and/or presence of BOP and/or suppuration, during any of the subsequent recall evaluations) and significant reductions in CRP levels over time [(T1: RC = 3.64 ± 2.13 and IC = 3.92 ± 2.02 mg/L) and (T3: RC = 2.12 ± 1.39 mg/L and IC = 3.71 ± 1.82 mg/L)]. Logistic regression analysis demonstrated that individuals with periodontitis recurrence presented 2.19 higher chances of presenting altered CRP levels (values ≥3 mg/L- T2 to T3) than those without periodontitis recurrence (95%CI:1.16-3.27; p = 0.017).

Conclusions: Higher CRP plasma levels were associated with higher recurrence of periodontitis and worse clinical periodontal parameters among IC when compared to RC.
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http://dx.doi.org/10.1111/jcpe.13407DOI Listing
March 2021

Benserazide as a potential novel fetal hemoglobin inducer: an observational study in non-carriers of hemoglobin disorders.

Blood Cells Mol Dis 2021 Mar 5;87:102511. Epub 2020 Nov 5.

Division of Hematology, University of Washington, Seattle, USA. Electronic address:

Induction of fetal hemoglobin production with hydroxyurea is an effective strategy in sickle cell disease and beta thalassemias, but up to 20% of patients do not respond to or cannot tolerate it. Benserazide is used in the treatment of Parkinson's disease and was noticed to induce gamma globin in preclinical models. We hypothesized that chronic treatment with benserazide-containing medication may be associated with increase in HbF production and in circulating F-cells. Blood samples were collected from 50 subjects including 35 patients on benserazide for Parkinson's disease, 10 healthy controls, and 5 patients with sickle cell anemia as positive controls for high fetal hemoglobin. We found a strong correlation between HbF and circulating F-cells in the entire population, but we found no significant increase in HbF and F-cell percentage in patients taking benserazide up to 700 mg daily. No hematologic abnormalities attributable to benserazide use after up to 22 years were detected. Our data support long-term safety and tolerability of benserazide at doses ten times higher than used in preclinical models to induce fetal hemoglobin. Further clinical trials enrolling patients with sickle cell disease and thalassemia are warranted to provide insight into its efficacy to treat those populations.
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http://dx.doi.org/10.1016/j.bcmd.2020.102511DOI Listing
March 2021

Clinical and microbiological effects of non-surgical periodontal treatment in individuals with rheumatoid arthritis: a controlled clinical trial.

Odontology 2021 Apr 3;109(2):484-493. Epub 2020 Nov 3.

Department of Dental Clinics, Oral Pathology, and Oral Surgery, Department of Periodontology, Faculty of Dentistry, Federal University of Minas Gerais, Antônio Carlos Avenue, 6627, Pampulha, PO Box 359, Belo Horizonte, Minas Gerais, 31270-901, Brazil.

The effect of periodontal treatment on clinical, microbiological and serological parameters of patients with rheumatoid arthritis (RA) are scarce and controversial. The aim of this study was to investigate the influence of non-surgical periodontal treatment on clinical periodontal status, subgingival bacterial levels of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola and RA activity through a controlled clinical trial on individuals with RA and periodontitis (PE). From a convenience sample, 107 individuals were considered eligible and consecutively allocated in four groups: (1) individuals without PE and RA (- PE-RA, n = 30); (2) individuals without PE and with RA (- PE + RA, n = 23); (3) individuals with PE and RA (+ PE + RA, n = 24); and (4) individuals with PE and without RA (+ PE-RA, n = 30). Full-mouth periodontal clinical examinations, microbiological analysis and Disease Activity Score (DAS-28) evaluations were performed at baseline (T1) and 45 days after non-surgical periodontal treatment (T2). At T1, individuals + PE + RA showed greater severity of PE than + PE-RA individuals. At T2, significant reductions were observed in all periodontal clinical parameters in both groups (p < 0.001) with a significant reduction in DAS-28 in + PE + RA (p = 0.011). Individuals + PE-RA and + PE-RA showed significant reductions for all bacteria (p < 0.001). Additionally, P. gingivalis demonstrated an expressively significant reduction in + PE + RA (p < 0.001). Non-surgical periodontal treatment was effective on improving the clinical periodontal condition, improving the RA clinical status and reducing the presence of periodontal pathogens. Brazilian Registry of Clinical Trials (ReBEC) protocol #RBR-8g2bc8 ( https://www.ensaiosclinicos.gov.br/rg/RBR-8g2bc8/ ).
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http://dx.doi.org/10.1007/s10266-020-00566-0DOI Listing
April 2021

Pterygium Surgery with Conjunctival Autograft Fixation Using Bipolar Electrocauterization.

Eur J Ophthalmol 2020 Oct 28:1120672120965488. Epub 2020 Oct 28.

Department of Ophthalmology and Visual Sciences, Paulista School of Medicine/Federal University of São Paulo (EPM/UNIFESP), São Paulo/SP, Brazil.

Purpose: To report a case series of pterygium surgery with conjunctival autograft fixation using bipolar electrocautery.

Design: A noncomparative, retrospective, interventional case series of pterygium surgery with follow-up longer than 12 months to assess recurrence and other complication rates.

Participants: Fifty-six eyes of 37 patients were treated between April 2011 and January 2018, either for primary ( = 53 cases) or recurrent ( = 3 cases) pterygia.

Intervention: After pterygium excision, free conjunctival grafts from the inferior bulbar conjunctiva of the same eye were harvested and fixated with the use of bipolar electrocautery.

Main Outcome Measure: Recurrence of the pterygium and complications.

Results: The mean follow-up was 41 months (range 12 to 81 months). There were no intraoperative complications. Recurrence of the lesion was seen in three eyes (5.36%). There were no other postoperative complications such as graft detachment, or formation of dellen or granulomas.

Conclusion: Conjunctival autograft fixation using bipolar electrocautery seems to be a fast, costly and safe procedure that can be applied in most cases of pterygium surgery.
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http://dx.doi.org/10.1177/1120672120965488DOI Listing
October 2020

Impact of oral lesions on the quality of life of psoriatic individuals: A case-control study.

Oral Dis 2020 Oct 26. Epub 2020 Oct 26.

Department of Dental Clinics, Oral Pathology, and Oral Surgery, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Objectives: To assess the presence of oral lesions and the impact of oral health-related quality of life (OHRQoL) on individuals with psoriasis.

Methods: This case-control study comprised 295 individuals with psoriasis and 359 controls. Oral examination to assess different types of oral lesions as angular cheilitis (AC), geographic tongue (GT), white (WP), and red plaque or red macule (RPM) was performed. To evaluate OHRQoL, the Oral Impact on Daily Performance (OIDP) questionnaire was applied. Data were analyzed using the chi-squared, Fisher, Kruskal-Wallis, Mann-Whitney, and Bootstrap Intervals tests.

Results: Individuals with psoriasis had significantly more oral lesions than controls (OR = 3.66, 95% CI: 2.33-5.85; p < .001) and higher global OIDP scores (12.17 case versus 6.93 controls; p = .008). Higher occurrence of GT (p < .001) and AC (p < .001) was observed in individuals with psoriasis. The final multivariate model demonstrated higher OIDP scores related to the following variables: alcohol use, diabetes, anxiolytics use, AC, and GT, showing worse OHRQoL.

Conclusion: Psoriatic individuals had a higher frequency of AC and GT than controls. Worse OIDP scores in frequency and severity were observed in psoriatic individuals with oral lesions, revealing the negative impacts of these lesions on OHRQoL.
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http://dx.doi.org/10.1111/odi.13695DOI Listing
October 2020

Periodontitis and the impact of oral health on the quality of life of psoriatic individuals: a case-control study.

Clin Oral Investig 2021 May 21;25(5):2827-2836. Epub 2020 Sep 21.

Department of Dental Clinics, Oral Pathology, and Oral Surgery, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

Aim: To evaluate the periodontal condition and the impact of oral health on the quality of life (OHRQL) among individuals with and without psoriasis.

Methods: This case-control study comprised 295 individuals with psoriasis and 359 controls. A full mouth examination was performed for all periodontal clinical parameters. To evaluate OHRQL, the Oral Impact on Daily Performance (OIDP) questionnaire was applied. Data was analyzed using the chi-square, Fischer, Kruskal-Wallis, Mann-Whitney, and Bootstrap intervals tests to determine different profiles in relation to the OIDP.

Results: Individuals with psoriasis had a 1.40 greater chance of having periodontitis than controls (OR = 1.40 95%CI: 1.01-1.93; p = 0.019). Individuals with psoriasis with periodontitis (+P) had greater impacts on OHRQL (13.76 ± 15.58), when compared with those without periodontitis (-P) (4.83 ± 8.25; p < 0.001). Additionally, psoriasis +P stage III/IV patients (13.94 ± 15.68) had worse indicators than controls -P (9.49 ± 22.54; p = 0.001). The final multivariate model demonstrated higher OIDP scores related to the following variables: diabetes, anxiolytics use, periodontitis, and psoriasis, showing worse OHRQoL.

Conclusions: This study demonstrated an important risk association between psoriasis and periodontitis, as both diseases demonstrated worse OHRQL indicators. Moreover, the severity of periodontitis and psoriasis significantly increased these negative impacts.

Clinical Relevance: Practical implications: Multidisciplinary interaction is desirable to improve the impact of these diseases on the QoL of individuals with psoriasis and periodontitis.
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http://dx.doi.org/10.1007/s00784-020-03600-1DOI Listing
May 2021

CXCR4 effector neutrophils in sickle cell anemia: potential role for elevated circulating serotonin (5-HT) in CXCR4 neutrophil polarization.

Sci Rep 2020 08 31;10(1):14262. Epub 2020 Aug 31.

Hematology Center, University of Campinas - UNICAMP, Rua Carlos Chagas 480, Cidade Universitária, Campinas, SP, 13083-878, Brazil.

Leukocyte recruitment and heterocellular aggregate formation drive the inflammatory vaso-occlusive processes associated with sickle cell anemia (SCA). We characterized neutrophils in a population of patients with SCA and investigated whether platelet-derived molecules can induce phenotypic alterations in this cell type. Imaging flow cytometry analysis demonstrated that the frequency of circulating CXCR4 neutrophils was significantly higher in steady-state SCA individuals than in healthy control individuals and that these cells presented increased CD11b activation and toll-like receptor-4 expression. SCA neutrophils display increased neutrophil-platelet aggregation, and CXCR4 neutrophils demonstrated augmented neutrophil-platelet aggregate frequency with a higher mean number of platelets adhered per neutrophil. Importantly, incubation of neutrophils with platelets significantly elevated their CXCR4 expression, while SCA plasma was found to induce CXCR4 neutrophil polarization significantly more than control plasma. SCA individuals had significantly increased plasma levels of serotonin (5-HT), and serotonin molecule and SCA plasma induced neutrophil CXCR4 expression in a serotonin-receptor-dependent manner. Thus, the augmented CXCR4 neutrophil population may contribute to mechanisms that promote vaso-occlusion in SCA; furthermore, circulating serotonin, derived from platelet activation, may play a role in the polarization of neutrophils, suggesting that serotonin-receptor antagonists or serotonin reuptake inhibitors could represent therapeutic approaches to reduce neutrophil activation in SCA.
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http://dx.doi.org/10.1038/s41598-020-71078-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459317PMC
August 2020

Association Between Sense of Coherence and Periodontal Outcomes: A Systematic Review and Meta-analysis.

Fam Community Health 2020 Aug 24. Epub 2020 Aug 24.

Departments of Periodontology (Messrs Cruz Olivo, Storino, and Pereira, Ms Moura, and Drs Miranda Cota and Costa) and Child's and Adolescent's Oral Health (Ms Corradi-Dias and Drs Paiva and Abreu), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; and Department of Population & Patient Health, King's College London, United Kingdom (Dr Abreu).

This systematic review and meta-analysis aimed to evaluate the association between sense of coherence (SOC) and periodontal outcomes. Electronic searches were performed in 6 databases. Seventeen studies that evaluated the association between SOC and periodontal outcomes were included. The included studies demonstrated that individuals with a stronger SOC were more likely to present improved periodontal outcomes. The meta-analysis showed that individuals with a lower SOC were 3.31 times more likely to present bleeding on probing. Sons/daughters of mothers with a lower SOC were 3.22 times more likely to present gingival bleeding. Individuals with a stronger SOC have better periodontal health.
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http://dx.doi.org/10.1097/FCH.0000000000000277DOI Listing
August 2020

Blood Flow Restriction Training Blunts Chronic Kidney Disease Progression in Humans.

Med Sci Sports Exerc 2021 02;53(2):249-257

Graduate Program in Physical Education, Catholic University of Brasilia, Brasilia, BRAZIL.

Purpose: This study aimed to verify the effect of 6 months of periodized resistance training (RT) with and without blood flow restriction (BFR) in patients with stage 2 chronic kidney disease (CKD) on glomerular filtration rate (GFR), uremic parameters, cytokines, and klotho-fibroblast growth factor 23 (FGF23) axis.

Methods: A total of 105 subjects were randomized in three groups of 35 each: control (CTL), RT, and RT + BFR. A first visit was required for an anamnesis to evaluate the number of medications and anthropometric measurements (body weight, height, and body mass index). Muscle strength (one-repetition maximum) was assessed. Venous blood samples were collected at baseline and after 6 months of training in all patients for the analysis of markers of renal function and integrity, as well as for the determination of the inflammatory profile. Statistical significances were adopted with P < 0.05.

Results: Both training therapies attenuated the decline of GFR (P < 0.05). The majority of CTL patients declined to stage 3 CKD (88.5%), whereas fewer incidents were noted with RT (25.7%) and RT + BFR (17.1%). Improved uremic parameters as well as inflammation (IL-6, IL-10, IL-15, IL-17a, IL-18, and TNF-α) and klotho-FGF23 axis in RT and RT + BFR (P < 0.05) were observed. Monocyte chemoattractant protein 1 was not changed (P > 0.05) but presented a large effect size (Cohen's d), demonstrating a propensity for improvement.

Conclusion: Six months of periodized RT with and without BFR in patients with stage 2 CKD attenuated the progression of the disease by maintaining GFR, improving uremic parameters, cytokine profile regulation, and klotho-FGF23 axis.
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http://dx.doi.org/10.1249/MSS.0000000000002465DOI Listing
February 2021

Validation of the Brazilian version of the Halitosis Associated Life-Quality Test (HALT).

Braz Oral Res 2020 17;34:e098. Epub 2020 Aug 17.

Department of Clinic, Pathology and Dental Surgery, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

The present study aimed to validate (cross-culturally adapt and test psychometric properties) the Brazilian version of the Halitosis Associated Life-Quality Test (HALT). A process of translation and cross-cultural adaptation was conducted by a group of dental researchers. The first draft of the Brazilian Portuguese version was pre-tested on a sample of 33 individuals leading up to the final version of the questionnaire. The Brazilian version of the HALT (B-HALT) was applied to 100 individuals with halitosis (organoleptic score ≥ 2) and 100 individuals without halitosis (organoleptic score < 2). Exploratory factor analysis (EFA) was performed to evaluate the dimensionality of B-HALT. Cronbach's alpha (α) and interclass correlation coefficient (ICC) were used to measure its reliability. For convergent validity, Spearman's correlation was conducted between the B-HALT and the organoleptic scores. The discriminant validity was evaluated through the Mann-Whitney and Kruskal-Wallis tests. EFA confirmed the unidimensionality of B-HALT, which has also demonstrated excellent internal consistency (α = 0.96) and test-retest reliability (ICC = 0.93). There was a positive correlation between B-HALT and organoleptic scores (r = 0.33; p < 0.001). B-HALT was able to discriminate between the groups with and without halitosis measured by the organoleptic method (p < 0.001) and self-reported halitosis (p < 0.001). B-HALT has demonstrated to be a reliable and valid tool to evaluate the oral health-related quality of life associated to halitosis in Brazilian adults.
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http://dx.doi.org/10.1590/1807-3107bor-2020.vol34.0098DOI Listing
October 2020

Clinical trials sponsored by industry and other private organizations.

Braz Oral Res 2020 7;34 Suppl 2:e077. Epub 2020 Aug 7.

Office of Graduate Studies and Scientific Affairs, Universidade de Taubaté, Taubaté, SP, Brazil.

The present manuscript discussed some relevant aspects related to private sponsored clinical trials in dentistry. For decades, the academy has been the major responsible for research in Brazil. Distant from the trade sector, academic research has not always provided clear benefits to society. A key aspect of making benefits clearer is the process of scientific knowledge transference to decision-makers, which is, in fact, the ground of evidence-based dentistry. Although private sponsoring of clinical research seems to be part of the research progress of the business rates, investment in Brazil is lower than those observed in other countries. It is particularly important to understand that instead of creating its own rules, dentistry imported the high-quality standards originally designed for pharmaceutical studies. Therefore, it is critical to understand the original rules and how dental items are classified by regulatory agencies. In fact, knowledge about international and local regulation is a basic assumption in industry-sponsored research. Despite globalization, the identification of industry-sponsored studies through open access databases is still very hard and time-demanding. A common concern when conducting industry-sponsored trials is study biases. Fortunately, many relevant organizations, academic and industry groups, have been working seriously against that. Finally, for less experienced researchers, many aspects related to industry-sponsored studies - such as confidentiality, authorship, budget - are deeply discussed until a final version of the trial agreement can be written and signed, protecting all sides. In short, the scenario should be improved, but it already represents a nice opportunity for dental research.
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http://dx.doi.org/10.1590/1807-3107bor-2020.vol34.0077DOI Listing
September 2020

Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria.

Hematol Transfus Cell Ther 2020 Jul 6. Epub 2020 Jul 6.

Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas, (HEMOCENTRO-UNICAMP), Campinas, SP, Brazil; Instituto Nacional de Ciência e Tecnologia do Sangue (INCT-S), Campinas, SP, Brazil.

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.
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http://dx.doi.org/10.1016/j.htct.2020.06.006DOI Listing
July 2020