Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

Abstract

Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy.

Methods

We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY.

Results

We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction.

Conclusion

Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

     

Inflammation response and liver stiffness: predictive model of regression of hepatic stiffness after sustained virological response in cirrhotics patients with chronic hepatitis C

Clinical and Experimental Medicine - Cirrhotic patients with chronic hepatitis C should be monitored for the evaluation of liver function and screening of hepatocellular carcinoma even after...     

Skeletal development of Kinosternon scorpioides limbs (Chelonia: Kinosternidae)

The morphological study of limbs is important for the understanding of tetrapod biology, where it can be applied to taxonomy and phylogeny, as well ecology and behavior. In this study area, osteogenesis is a subject in Kinosternidae, which has been little researched. The main aim of this study was to characterize the skeletogenesis of Kinosternon scorpioides limbs. Samples were histologically processed, and the embryos were cleared with potassium hydroxide and stained with alcian blue and alizarin red. It was observed that the limbs arose in embryonic Stage 10 as mesenchymal condensate cells. The first stylopodium chondrification centers were noted at Stage 14. Zeugopodium chondrification centers appeared at Stage 15; carpal, metacarpal, tarsal, and metatarsal regions were observed at Stage 16, and the cartilage molds of all bones limbs were present at Stage 18. Ossification began in the humerus and femur at Stage 20, and continued into the radius, ulna, tibia, and fibula bones. By Stage 23, it was already effectively directed toward the bone epiphyses in both limbs. At Stage 26 and hatching, only articular cartilages remained, and in the majority of samples the carpal region showed no affinity for alcian blue or alizarin red staining. This study acts as an indicative parameter of the taxon's normal development and can contribute to the phylogenetic understanding of this group.     

Biological and physicochemical implications of the aging process on titanium and zirconia implant material surfaces

Statement of problemChanges in physicochemical properties because of implant material aging and natural deterioration in the oral environment can facilitate microbial colonization and disturb the soft-tissue seal between the implant surfaces.PurposeThe purpose of this in vitro study was to investigate the effect of aging time on the physicochemical profile of titanium (Ti) and zirconia (ZrO₂) implant materials. Further microbiology and cell analyses were used to provide insights into the physicochemical implications of biological behavior.Material and methodsDisk-shaped specimens of Ti and ZrO₂ were submitted to roughness, morphology, and surface free energy (SFE) analyses before nonaging (NA) and after the aging process (A). To simulate natural aging, disks were subjected to low-temperature degradation (LTD) by using an autoclave at 134 ºC and 0.2 MPa pressure for 20 hours. The biological activities of the Ti and ZrO₂ surfaces were determined by analyzing Candida albicans (C. albicans) biofilms and human gingival fibroblast (HGF) cell proliferation. For the microbiology assays, a variance analysis method (ANOVA) was used with the Tukey post hoc test. For the evaluation of cellular proliferation, the Kruskal-Wallis test followed by Dunn multiple comparisons were used.ResultsTi nonaging (TNA) and ZrO₂ nonaging (ZNA) disks displayed hydrophilic and lipophilic properties, and this effect was sustained after the aging process. Low-temperature degradation resulted in a modest change in intermolecular interaction, with 1.06-fold for TA and 1.10-fold for ZA. No difference in biofilm formation was observed between NA and A disks of the same material. After 48 hours, the viability of the attached HGF cells was very similar to that in the NA and A groups, regardless of the tested material.ConclusionThe changes in the physicochemical properties of Ti and ZrO₂ induced by the aging process do not interfere with C. albicans biofilm formation and HGF cell attachment, even after long-term exposure.     

Accuracy of CAD-CAM systems for removable partial denture framework fabrication: A systematic review

Statement of problemRemovable partial dentures (RPDs) are traditionally made by casting, a complex, error-prone, and time-consuming process. Computer-aided design and computer-aided manufacturing (CAD-CAM) RPD systems may simplify the clinical steps and minimize errors; however, the accuracy of CAD-CAM RPD systems is unclear.PurposeThe purpose of this systematic review was to determine whether CAD-CAM systems are accurate for the manufacturing of RPD frameworks.Material and methodsA literature search was conducted through Medline-PubMed, Scopus, Lilacs, Web of Science, and Cochrane Library databases using specific keywords for articles published up to November 2019. Three reviewers obtained data and compared the results. All studies evaluated the framework accuracy or fit of prostheses fabricated with conventional and digital techniques.ResultsA total of 7 articles, 2 clinical studies, and 5 in vitro studies that complied with the inclusion criteria were evaluated. One in vitro study compared indirect (extraoral) and direct (intraoral) scanning for partially edentulous ridges and shows that digital scans were better than conventional impressions in terms of trueness. In the other studies included, although the frameworks analyzed had clinically acceptable discrepancies (<311 μm), the material influenced the fit. Polyetheretherketone (PEEK) showed better fit than traditional metal cast RPDs. Co-Cr alloy RPDs produced by rapid prototyping exhibited the highest discrepancies when produced by sintering laser melting.ConclusionsThe results show that the digital technique for RPD frameworks is accurate. In the studies included, the analyzed frameworks had clinically acceptable gaps, but the results were heterogeneous among studies because the articles used different measurement methods with small sample sizes. Few studies discussed the long-term clinical performance. The digital technique for RPD frameworks was accurate because the misfits and mismatches found in in vitro and clinical studies were within the acceptable clinical limit for RPDs.     

Recommendations for Managing Endodontic Emergencies during Coronavirus Disease 2019 Outbreak

IntroductionThe management of endodontic emergencies has been particularly challenging during the coronavirus disease 2019 (COVID-19) outbreak because of the possible generation of airborne particles and aerosols. The aim of this report was to contribute to the practice of endodontics by proposing a general protocol for the management of emergencies showing the rationale for remote diagnosis, clinical procedures, and the use of personal protective equipment and barriers at the dental office during the COVID-19 outbreak.MethodsA review of the literature was conducted up to May 2020 on relevant institutional sites, aiming to retrieve the best updated evidence. The reporting considered the Reporting Tool for Practice Guidelines in Health Care statement.ResultsRecommendations from Cochrane Oral Health, the American Dental Association, and the Centers for Disease Control and Prevention were included along with the American Association of Endodontists resources and scientific articles that addressed the issue.ConclusionsThe proposed protocol could contribute to the management of endodontic emergencies at the dental office during the COVID-19 outbreak.     

Maternal Apical Periodontitis Increases Insulin Resistance and Modulates the Antioxidant Defense System in the Gastrocnemius Muscle of Adult Offspring

IntroductionMaternal apical periodontitis (AP) is associated with insulin resistance (IR) in adult offspring. Oxidative stress has been linked to IR. This study investigated insulin sensitivity (IS) and oxidative stress in the gastrocnemius muscle (GM) of adult offspring of rats with AP.MethodsFifteen female Wistar rats were distributed into a control group, a group with 1 tooth with AP, and a group with 4 teeth with AP. Thirty days after AP induction, female rats were mated with healthy male rats. When male offspring reached 75 days of age, glycemia, insulinemia, and IS were determined. In the GM, the oxidative damage products (thiobarbituric acid reactive substances and carbonyl protein) and activities of enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) and nonenzymatic (glutathione and total antioxidant capacity) antioxidants were quantified. Analysis of variance was performed followed by the Tukey post hoc test (P < .05).ResultsMaternal AP was associated with decreased IS and changes in antioxidant activities (reduced superoxide dismutase and increased catalase, glutathione peroxidase, and glutathione) and decreased thiobarbituric acid reactive substance concentration in the GM of their adult offspring. However, maternal AP does not appear to affect glycemia, carbonyl protein concentration, and the nonenzymatic total antioxidant capacity in the GM of this offspring.ConclusionsMaternal AP modulates the antioxidant defense system in the GM of their adult offspring, attenuating lipid peroxidation in this tissue. This reflects part of an adaptive response of the offspring to the stimulation of the maternal chronic oral inflammatory process in which the organism acts by decreasing oxidative tissue damage in the postnatal stage. The present study improves knowledge about the impact of maternal oral inflammation on healthy offspring.     

Extended glaze firings for porcelain-veneered zirconia: Effects on the mechanical and optical behavior

ObjectiveThis study evaluated the effect of dwell time (conventional or extended) and cooling protocol (fast or slow) of self-glaze firings on the mechanical (flexural strength and crack propagation) and optical (color and translucency) properties of a porcelain-veneered zirconia system.MethodsBilayer disc-shaped samples were prepared (Vita VM9 + In-Ceram YZ) and divided according to the final thermal treatment: glaze firing followed by slow cooling (furnace opening at 200 °C) (G-S) or fast cooling (furnace opening at 600 °C) (G-F, manufacturer-recommended protocol), extended glaze firing (15 min of dwell time) followed by slow cooling (EG-S) or fast cooling (EG-F), or no thermal treatment (CTRL). Porcelain roughness (Ra and Rz) was measured before and after glaze firings. Color (ΔE₀₀) and translucency (TP₀₀) alteration were also evaluated. Flexural strength was measured with the piston-on-three-ball test and crack propagation analysis was performed after Vickers indentations. Complementary analyzes of crystalline phase and scanning electron microscopy were carried out.ResultsSignificant effect of dwell time was observed, with extended glaze leading to higher flexural strength and shorter crack lengths. Cracks of EG groups were observed to end in clusters of crystals. Color and translucency changed below perceptibility thresholds. All treatments led to a smoother surface and EG groups reached the lowest Rz values. An extra SiO₂ peak was revealed in control and EG groups. No effect of cooling protocol was found.SignificanceExtended glaze firing was able to improve the resistance to crack initiation and propagation of porcelain-veneered zirconia without clinically perceptible changes in optical properties.