Losartan and enalapril maleate differently influence SARS-CoV-2-infected vero cells.

BACKGROUND: The COVID-19 pandemic has posed significant challenges to global healthcare systems, particularly impacting individuals with pre-existing conditions like hypertension. This study sought to assess the impact of the antihypertensive medications, losartan and enalapril maleate on SARS-CoV-2 infected cells. Vero E6 cells were infected and treated in vitro, evaluating cell viability via the MTT colorimetric assay. Additionally, the study measured relative levels of viral RNA and selected gene messenger RNAs using reverse transcriptase followed by quantitative real-time polymerase chain reaction. RESULTS: The findings revealed that losartan substantially reduced nucleocapsid RNA levels of SARS-CoV-2 to nearly undetectable levels, while enalapril maleate did not demonstrate a significant effect. In response to viral infection, the expression of il-18, p53, p21, and p62 increased compared to uninfected-untreated cells. Notably, il-6 expression was upregulated by both infection and treatments. A comparison between infected cells treated with losartan or enalapril maleate highlighted the presence of distinct profiles in the expression of il-6, p53, p21, and p62. CONCLUSIONS: The data from our study suggest that these medications could interfere with certain effects triggered by SARS-CoV-2 infection in Vero E6 cells. However, their influence appears to vary both quantitatively and qualitatively in the modulation of metabolic and signal transduction pathways.

Identification of antimycobacterial 8-hydroxyquinoline derivatives as in vitro enzymatic inhibitors of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase.

The increasing prevalence of drug-resistant Mycobacterium tuberculosis strains stimulates the discovery of new drug candidates. Among them are 8-hydroxyquinoline (8HQ) derivatives that exhibited antimicrobial properties. Unfortunately, there is a lack of data assessing possible targets for this class mainly against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), a validated target in this field. Thus, the main purpose of this study was to identify 8HQ derivatives that are active against M. tuberculosis and MtInhA. Initially, the screening against the microorganism of a small antimicrobial library and its new derivatives that possess some structural similarity with MtInhA inhibitors identified four 7-substituted-8HQ (series 5 - 5a, 5c, 5d and 5i) and four 5-substituted-8HQ active derivatives (series 7 - 7a, 7c, 7d and 7j). In general, the 7-substituted 8-HQs were more potent and, in the enzymatic assay, were able to inhibit MtInhA at low micromolar range. However, the 5-substituted-8-HQs that presented antimycobacterial activity were not able to inhibit MtInhA. These findings indicate the non-promiscuous nature of 8-HQ derivatives and emphasize the significance of selecting appropriate substituents to achieve in vitro enzyme inhibition. Finally, 7-substituted-8HQ series are promising new derivatives for structure-based drug design and further development.

Rp3: Ribosome profiling-assisted proteogenomics improves coverage and confidence during microprotein discovery.

There has been a dramatic increase in the identification of non-canonical translation and a significant expansion of the protein-coding genome. Among the strategies used to identify unannotated small Open Reading Frames (smORFs) that encode microproteins, Ribosome profiling (Ribo-Seq) is the gold standard for the annotation of novel coding sequences by reporting on smORF translation. In Ribo-Seq, ribosome-protected footprints (RPFs) that map to multiple genomic sites are removed since they cannot be unambiguously assigned to a specific genomic location. Furthermore, RPFs necessarily result in short (25-34 nucleotides) reads, increasing the chance of multi-mapping alignments, such that smORFs residing in these regions cannot be identified by Ribo-Seq. Moreover, it has been challenging to identify protein evidence for Ribo-Seq. To solve this, we developed Rp3, a pipeline that integrates proteogenomics and Ribosome profiling to provide unambiguous evidence for a subset of microproteins missed by current Ribo-Seq pipelines. Here, we show that Rp3 maximizes proteomics detection and confidence of microprotein-encoding smORFs.

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection.

Tuberculosis is a disease caused by a single pathogen that leads to a death toll estimated to be more than a million per year. Mycobacterium tuberculosis (Mtb), which affects mainly the lungs, spreads by airborne transmission when infectious respiratory particles from an infected human enter the respiratory tract of another person. Despite diagnosis and treatment being well established, the rise of cases of patients infected with Mtb strains with multidrug resistance to the antibiotics used in the regimen against the disease is alarming. Indole used as a core molecule has been described as a promising structure to treat several diseases. 5-Fluoroindole (5-FI) compound, evaluated in the free base and in the hydrochloride (5-FI.HCl) forms, inhibited the growth of pan-sensitive Mtb H37Rv strain in the same range (4.7-29.1 µM) of clinical isolates that have resistance to at least two first-line drugs. Although 5-FI showed no cytotoxicity in Vero and HepG2 cells, high permeability (2.4.10-6 cm/s) in the PAMPA assay, and high metabolic stability (Clint 9.0 mL/min/kg) in rat liver microsomes, limited solubility at plasmatic and intestinal pH values prompted formation and employment of its salt form (5-FI.HCl). Although the 5-FI.HCl compound showed increased solubility at pH values of 7.4 and 9.1 and increased stability in aqueous solutions, data for intrinsic clearance (Clint = 48 mL/min/kg) and a half-life (t 1/2 = 12 min) showed decreased metabolic stability. As 5-FI.HCl showed both good absorption and ability to reach the systemic circulation of animals without the need to use vehicles containing cosolvents or surfactants, it was chosen to evaluate its effectiveness in the model of tuberculosis in mice. The in vivo results showed the concentration of the compound in plasma increasing within 30 min in the systemic circulation and the capacity of reducing the Mtb burden in the lungs at the concentration of 200 µmol/kg after 21 days of infection, with no toxicity in mice.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

Exploring Scaffold Hopping for Novel 2-(Quinolin-4-yloxy)acetamides with Enhanced Antimycobacterial Activity.

Utilizing a scaffold-hopping strategy from the drug candidate telacebec, a novel series of 2-(quinolin-4-yloxy)acetamides was synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (Mtb) growth. These compounds demonstrated potent activity against drug-sensitive and multidrug-resistant strains (MIC ≤ 0.02 µM). Leading compounds were evaluated against a known qcrB resistant strain (T313A), and their loss in activity suggested that the cytochrome bc1 complex is the likely target. Additionally, these structures showed high selectivity regarding mammalian cells (selectivity index > 500) and stability across different aqueous media. Furthermore, some of the synthesized quinolines demonstrated aqueous solubility values that exceeded those of telacebec, while maintaining low rates of metabolism. Finally, a selected compound prevented Mtb growth by more than 1.7 log10 colony forming units in a macrophage model of tuberculosis (TB) infection. These findings validate the proposed design and introduce new 2-(quinolin-4-yloxy)acetamides with potential for development in TB drug discovery campaigns.

Deucravacitinib for Moderate-to-Severe Psoriasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is contrasting evidence regarding the efficacy and safety of JAK (Janus kinase) inhibitors in the treatment of psoriasis. This systematic review and meta-analysis assessed deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, as the therapy of choice for moderate-to-severe psoriasis. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials, including patients with moderate-to-severe psoriasis. Outcomes of interest were serious adverse events (SAEs), the severity of illness, as measured by the validated questionnaires: Psoriasis Area and Severity Index (PASI) and scalp-specific Physician's Global Assessment (ss-PGA); and quality of life, measured by the Dermatology Life Quality Index (DLQI). Four studies with 1663 patients were included in the meta-analysis, of whom 1123 (67.5%) were treated with deucravacitinib during a 12-to-16-week follow-up. The mean age was 45.4 ± 13.3 years, and 70.2% were male. Two-thirds had a history of scalp psoriasis. Achievement of PASI 75 was significantly higher in the deucravacitinib group, as compared with placebo (RR 5.7; 95% CI 4.32-7.53; P<0.001). Similarly, ss-PGA 0/1 (RR 3.86; 95%CI 3.02-4.94; P<0.001) and DLQI 0/1 (RR 3.89; 2.89-5.22; P<0.001) were also significantly more frequent in the deucravacitinib group. The incidence of SAEs was similar between groups. These findings suggest that patients with moderate-to-severe psoriasis treated with deucravacitinib for 12 to 16 weeks had significantly decreased severity of illness and improved quality of life, without a concerning increase in the incidence of SAEs. J Drugs Dermatol. 2024;23(2):67-73.  doi:10.36849/JDD.7539.

Fatigue resistance of monolithic and multilayer zirconia crowns using veneer layering or CAD-on technique.

This study aims to evaluate the fatigue resistance of monolithic zirconia (Yz) and multilayer ceramic structures using the CAD-on technique in different thicknesses. Fifty (N=50) standardized single crowns preparations were made in fiberglass-reinforced epoxy resin (NEMA grade G10), digitalized, and restorations were machined in CAD-CAM, composing 5 groups (n= 10): Control: 1.5 mm (milled zirconia framework + manual layered porcelain); Yz monolithic 1.5 mm; Yz monolithic 1.0 mm; CAD-on 1.5 mm; and CAD-on 1.0 mm (milled zirconia framework 0.5 mm thickness bonded by a low fuse ceramic to a milled lithium disilicate layer of 1.0 mm or 0.5 mm, respectively). The G10 bases were conditioned with 10% hydrofluoric acid; the crowns were air abraded with 110 µm alumina particles; and then luted onto each other with self-adhesive resin cement. A cyclic fatigue test was performed (initial load: 400N for 10,000 cycles, frequency of 20 Hz, step size of 200N) until failure, and the data was submitted to a survival statistical analysis. No failures were observed at Yz monolithic 1.5 mm. High and similar performance was observed for Cad-On groups and Yz monolithic 1.0 mm. The control group depicted the worst behavior. The Weibull modulus of CAD-on 1.5 mm was higher than the control while being similar to the other conditions. Both the monolithic systems and the CAD-on technique showed high and similar fatigue fracture behavior and survival rates, which were also higher than the control bilayer system. Both systems reduced the occurrence of delamination failures, making them suitable for clinical use.

The Integration of Proteogenomics and Ribosome Profiling Circumvents Key Limitations to Increase the Coverage and Confidence of Novel Microproteins.

There has been a dramatic increase in the identification of non-conical translation and a significant expansion of the protein-coding genome and proteome. Among the strategies used to identify novel small ORFs (smORFs), Ribosome profiling (Ribo-Seq) is the gold standard for the annotation of novel coding sequences by reporting on smORF translation. In Ribo-Seq, ribosome-protected footprints (RPFs) that map to multiple sites in the genome are computationally removed since they cannot unambiguously be assigned to a specific genomic location, or to a specific transcript in the case of multiple isoforms. Furthermore, RPFs necessarily result in short (25-34 nucleotides) reads, increasing the chance of ambiguous and multi-mapping alignments, such that smORFs that reside in these regions cannot be identified by Ribo-Seq. Here, we show that the inclusion of proteogenomics to create a Ribosome Profiling and Proteogenomics Pipeline (RP3) bypasses this limitation to identify a group of microprotein-encoding smORFs that are missed by current Ribo-Seq pipelines. Moreover, we show that the microproteins identified by RP3 have different sequence compositions from the ones identified by Ribo-Seq-only pipelines, which can affect proteomics identification. In aggregate, the development of RP3 maximizes the detection and confidence of protein-encoding smORFs and microproteins.

Sublobar resection versus lobectomy for stage IA non-small-cell lung cancer: A systematic review and meta-analysis of randomized controlled trials.

Surgical resection is the first-line treatment for early-stage lung cancer, with lobectomy being the standard choice since the 1960s. Nevertheless, recent studies have shown controversies about whether sublobar resection or lobectomy is the optimal surgical approach today. In this sense, this meta-analysis aims to compare these techniques. PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) comparing sublobar resection with lobectomy for stage IA non-small-cell lung cancer (NSCLC) and reporting any of the following outcomes: (1) Overall survival (OS); (2) disease-free survival (DFS); and (3) total disease recurrences. Sublobar resection encompassed wedge resection and segmentectomy techniques. A total of 1975 patients from four studies were included, of whom 978 (49.5%) underwent sublobar resection and 973 (49.3%) were male. All tumors were smaller than 2 cm. Follow-up ranged from 5 to 7.3 years. Mean age was 62.8 ± 37.0 years, and 1353 (68.5%) patients had a known smoking history. OS (HR 0.79; 95% CI 0.60-1.05; p = 0.11) and DFS (HR 1.02; 95% CI 0.86-1.22; p = 0.80) did not significantly differ between the sublobar resection and lobectomy groups. Similarly, no significant statistical difference was observed in total disease recurrences (RR 1.17; 95% CI 0.93-1.46; p = 0.17). Subgroup and isolated sublobar resection techniques analyses were not possible due to the lack of data. Sublobar resection and lobectomy have similar OS, DFS, and disease recurrence rates for stage IA NSCLC. These findings underline the need for new RCTs investigating these outcomes in specific patient subgroups and isolated sublobar resection techniques.

Progression of Chronic Kidney Disease in over 65-year-old Nephroprotection Program Patients in Colombia

Background: Studies evaluating chronic kidney disease in older adults are scarce despite the high prevalence of the disease in this age group. In this study we have tried to determine the factors associated with the progression of chronic kidney disease in a group of patients over 65 years old. Methods: An analytical observational study of a prospective non-concurrent cohort was performed. We included patients older than 65 years belonging to a nephroprotection program and then, we followed them for 12 months. The variables of interest were age, sex, history of diabetes mellitus, serum creatinine at baseline and at 12-month follow-up, blood pressure and use of antihypertensive drugs, high density lipoprotein and low density lipoprotein, cholesterol levels, proteinuria, and use of antiplatelet agents. The estimated glomerular filtration rate (eGFR) was calculated at baseline and at 12-month follow-up, lastly the progression of chronic kidney disease was established. Results: 200 patients were included with an average age of 78.9 + 7.6 years, 51 % (102) females, 33 % (66) with a history of diabetes mellitus, with a mean initial eGFR 38.8 + 12.1 mL/min/1.73 m2. The mean of the final eGFR was 36.4 + 11.0 mL/min/ 1.73 m2 ; 17.5 % (35) presented a decrease > 25 % of the initial eGFR (progression) and 37.5 % (75) showed a decrease > 5mL/min/1.73m2/ year (rapid progression). Progression and rapid progression were significantly associated with age (p = 0.03 and p = 0.001, respectively), male sex (p < 0.001 and p < 0.001, respectively) and proteinuria (p < 0.001 and p < 0.001, respectively). There were no significant associations with other variables of interest. Conclusion: In our study, the progression of chronic kidney disease in patients older than 65 years in a nephroprotection program was significantly associated with the increased age, male sex, and presence of proteinuria.

Antecedentes: los estudios que evalúan la enfermedad renal crónica en adultos mayores son escasos, a pesar de la alta prevalencia de esta enfermedad en este grupo de edad. En este estudio hemos intentado determinar los factores asociados a la progresión de la enfermedad renal crónica en un grupo de pacientes mayores de 65 años. Métodos: se realizó un estudio observacional analítico de una cohorte prospectiva no concurrente. Se incluyeron pacientes mayores de 65 años pertenecientes a un programa de nefroprotección y se les siguió durante 12 meses. Las variables de interés fueron edad, sexo, antecedentes de diabetes mellitus, creatinina sérica al inicio y a los 12 meses de seguimiento, presión arterial y uso de fármacos antihipertensivos, niveles de colesterol, lipoproteínas de alta densidad y lipoproteínas de baja densidad, proteinuria y uso de antiagregantes plaquetarios. La tasa de filtración glomerular estimada (TFGe) se calculó tanto al inicio como a los 12 meses de seguimiento y se estableció la progresión de la enfermedad renal crónica. Resultados: se incluyeron 200 pacientes con una edad promedio de 78,9 + 7,6 años, 51 % (102) mujeres, 33 % (66) con antecedentes de diabetes mellitus, con TFGe inicial promedio 38,8 + 12,1 mL/min/1,73 m2. La media del TFGe final fue de 36,4 + 11,0 mL/min/ 1,73 m2; El 17,5 % (35) presentó una disminución > 25 % del TFGe inicial (progresión) y el 37,5 % (75) presentó una disminución > 5mL/min/1,73m2/año (progresión rápida). La progresión y la progresión rápida se asociaron significativamente con la edad (p = 0,03 y p = 0,001, respectivamente), el sexo masculino (p < 0,001 y p < 0,001, respectivamente) y la proteinuria (p < 0,001 y p < 0,001, respectivamente). No hubo asociaciones significativas con otras variables de interés. Conclusión: en nuestro estudio, la progresión de la enfermedad renal crónica en pacientes mayores de 65 años en programa de nefroprotección se asoció significativamente con el aumento de la edad, el sexo masculino y la presencia de proteinuria.

SARS-CoV-2 immune complex triggers human monocyte necroptosis.

We analyzed the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) itself and SARS-CoV-2-IgG immune complexes to trigger human monocyte necroptosis. SARS-CoV-2 was able to induce monocyte necroptosis dependently of MLKL activation. Necroptosis-associated proteins (RIPK1, RIPK3 and MLKL) were involved in SARS-CoV-2N1 gene expression in monocytes. SARS-CoV-2 immune complexes promoted monocyte necroptosis in a RIPK3- and MLKL-dependent manner, and Syk tyrosine kinase was necessary for SARS-CoV-2 immune complex-induced monocyte necroptosis, indicating the involvement of Fcγ receptors on necroptosis. Finally, we provide evidence that elevated LDH levels as a marker of lytic cell death are associated with COVID-19 pathogenesis.

Fatigue performance analysis of strength-graded zirconia polycrystals for monolithic three-unit implant-supported prostheses.

The aim of this study was to evaluate the fatigue behavior of strength-graded zirconia polycrystals used as monolithic three-unit implant-supported prosthesis; complementarily, crystalline phase and micromorphology were also assessed. Fixed prostheses with 3 elements supported by 2 implants were confectioned, as follows: Group 3Y/5Y - monolithic structures of a graded 3Y-TZP/5Y-TZP zirconia (IPS e.max® ZirCAD PRIME); Group 4Y/5Y - monolithic structures of a graded 4Y-TZP/5Y-TZP zirconia (IPS e.max® ZirCAD MT Multi); Group Bilayer - framework of a 3Y-TZP zirconia (Zenostar T) veneered with porcelain (IPS e.max Ceram). The samples were tested for fatigue performance with step-stress analysis. The fatigue failure load (FFL), the number of cycles required until failure (CFF), and the survival rates in each cycle were recorded. The Weibull module was calculated and the fractography analyzed. The crystalline structural content via Micro-Raman spectroscopy and the crystalline grain size via Scanning Electron microscopy were also assessed for graded structures. Group 3Y/5Y showed the highest FFL, CFF, probability of survival, and reliability (based on Weibull modulus). Group 4Y/5Y showed significantly superior FFL and probability of survival than group bilayer. Fractographic analysis revealed catastrophic flaws in the monolithic structure and cohesive fracture of porcelain in bilayer prostheses, all originating from the occlusal contact point. The graded zirconia presented small grain size (≤0.61 µm), with the smallest values at the cervical region. The main composition of graded zirconia was of grains at tetragonal phase. The strength-graded monolithic zirconia, especially the 3Y-TZP/5Y-TZP, showed to be promising for use as monolithic three-unit implant-supported prosthesis.

Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation.

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of MtInhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-aminoquinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-resistant tuberculosis treatments.

Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase: molecular docking, in silico toxicity and in vitro experiments.

Tuberculosis (TB) is one of the main causes of death from a single pathological agent, Mycobacterium tuberculosis (Mtb). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of Mtb. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of Mtb. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from Mtb (MtSK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of MtSK according to the predicted binding energy. In vitro inhibitory activity of MtSK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive Mtb H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both MtSK and the in vitro growth of Mtb.

Is the adhesive or mechanical behavior of glass ceramics influenced by the adhesive layer application after etching and silanization? A literature review

Aim: This review investigated the effect of applying an adhesive after surface treatment of glass-ceramics on the bonding, mechanical or clinical behavior. Methods: Studies comparing the adhesive, mechanical or clinical behavior of glass-ceramics, with or without adhesive application after surface treatment, were included. Searches were performed in PubMed, Scopus, and Web of Sciences databases (January 2022), resulting in 15 included studies. Results: Regarding the evaluated outcomes, 13 studies assessed bond strength, 2 studies assessed biaxial flexural strength and 1 study assessed fatigue failure load, while no study evaluating clinical outcomes was included. It was possible to observe that the adhesive application after ceramic surface treatment was unfavorable or did not influence the evaluated outcomes. Conclusion: Most of the evidence available in the literature shows that the adhesive application after surface treatment does not improve the adhesive and mechanical behavior of glass-ceramics

Fatigue resistance of monolithic and multilayer zirconia crowns using veneer layering or CAD-on technique

Abstract This study aims to evaluate the fatigue resistance of monolithic zirconia (Yz) and multilayer ceramic structures using the CAD-on technique in different thicknesses. Fifty (N=50) standardized single crowns preparations were made in fiberglass-reinforced epoxy resin (NEMA grade G10), digitalized, and restorations were machined in CAD-CAM, composing 5 groups (n= 10): Control: 1.5 mm (milled zirconia framework + manual layered porcelain); Yz monolithic 1.5 mm; Yz monolithic 1.0 mm; CAD-on 1.5 mm; and CAD-on 1.0 mm (milled zirconia framework 0.5 mm thickness bonded by a low fuse ceramic to a milled lithium disilicate layer of 1.0 mm or 0.5 mm, respectively). The G10 bases were conditioned with 10% hydrofluoric acid; the crowns were air abraded with 110 μm alumina particles; and then luted onto each other with self-adhesive resin cement. A cyclic fatigue test was performed (initial load: 400N for 10,000 cycles, frequency of 20 Hz, step size of 200N) until failure, and the data was submitted to a survival statistical analysis. No failures were observed at Yz monolithic 1.5 mm. High and similar performance was observed for Cad-On groups and Yz monolithic 1.0 mm. The control group depicted the worst behavior. The Weibull modulus of CAD-on 1.5 mm was higher than the control while being similar to the other conditions. Both the monolithic systems and the CAD-on technique showed high and similar fatigue fracture behavior and survival rates, which were also higher than the control bilayer system. Both systems reduced the occurrence of delamination failures, making them suitable for clinical use.

Resumo Este estudo teve como objetivo avaliar o comportamento à fadiga de estruturas cerâmicas monolíticas de zircônia (Yz) e multicamadas utilizando a técnica CAD-on em diferentes espessuras. Cinquenta (N=50) preparos unitários padronizados foram confeccionados em resina epóxi reforçada com fibra de vidro (NEMA grau G10), digitalizados e as restaurações usinadas em CAD-CAM, compondo 5 grupos (n= 10): Controle: 1,5 mm (estrutura de zircônia fresada + porcelana estratificada manualmente); Yz monolítica 1,5 mm; Yz monolítica 1,0 mm; CAD-on em 1,5 mm; e CAD-on 1,0 mm (estrutura de zircônia fresada com 0,5 mm de espessura ligada por uma cerâmica de baixa fusão a uma camada de dissilicato de lítio fresado de 1,0 mm ou 0,5 mm, respectivamente). As bases do G10 foram condicionadas com ácido fluorídrico a 10%; as coroas foram jateadas com partículas de alumina de 110 μm; e então cimentadas uma sobre a outra com cimento resinoso autoadesivo. Foi realizado um teste de fadiga cíclica (carga inicial: 400N para 10.000 ciclos, frequência de 20 Hz, step de 200N) até a falha, e os dados foram submetidos a uma análise estatística de sobrevivência. Nenhuma falha foi observada para Yz monolítica de 1,5 mm. Desempenho alto e semelhante foi observado para os grupos Cad-On e Yz monolítica 1,0 mm. O grupo controle apresentou o pior comportamento. O módulo de Weibull do CAD-on 1,5 mm foi maior que o grupo controle, sendo semelhante às outras condições. Tanto os sistemas monolíticos quanto a técnica CAD-on apresentaram alto e semelhante desempenho mecânico e taxas de sobrevivência, que também foram superiores ao sistema bicamada de controle. Ambos os sistemas reduziram a ocorrência de falhas de delaminação, tornando-os adequados para uso clínico.

Influence of number and position of porcelain specimens in the furnace on flexural strength and translucency

The aim of this study was to investigate the influence of the quantity and positioning of feldspathic ceramic specimens inside the furnace on their flexural strength and translucency. The tested hypotheses were that the arrangement of specimens in the furnance would not influence 1) the translucency or 2) the biaxial strength of the porcelain. Methods: Ninety porcelain specimens were made (1.2 mm thickness and 13.5 mm diameter) and assigned into two main groups (n=15): G1 group - 15 firing cycles containing only one specimen each, always at the center of the refractory; and G5 group - 15 firing cycles containing five specimen each, where one specimen was at the center of the refractory and four specimens positioned equidistantly on the periphery. The translucency test was performed using a spectrophotometer, followed by the flexural strength test, according to ISO 6872:2015. T-student test was performed for both the mechanical and optical obtained data. Results: The flexural strength of the porcelain was not affected by the positioning (center x periphery) of the specimens inside the furnace (p =0.08), but the translucency was affected (periphery > center; p =0.009). Regarding to the number of feldspathic ceramic specimens, the biaxial flexural strength was affected (p =0.025), as well as the translucency (p <0.05). Conclusion: A higher quantity of feldspathic ceramic specimens for each firing cycle decreased its biaxial flexural strength and translucency. Also, specimens positioned at the center of the refractory became less translucent than those positioned at the periphery.

Influence of connector cross-sectional geometry on the load-bearing capacity under fatigue of implant-supported zirconia fixed partial prosthesis.

STATEMENT OF PROBLEM: Zirconia has been reported to be suitable for multiunit monolithic restorations. However, as the connector region is the weakest part of the system, studies are needed to determine the optimal connector geometry. PURPOSE: The purpose of this in vitro study was to evaluate the load-bearing capacity under fatigue of implant-supported fixed partial prostheses made of monolithic zirconia with different connector cross-sectional geometries. MATERIAL AND METHODS: Three-unit monolithic fixed partial prostheses (from mandibular second premolar to the second molar) were fabricated in zirconia (Zenostar T) by computer-aided design and computer-aided manufacture (CAD-CAM). Different connector cross-sectional geometries, with an area of 9 mm2, were tested (n=10): round, square with rounded angles, or trapezoid with rounded angles. The prostheses were screwed over 2 implants and inserted into acrylic resin bases. The specimens were submitted to a mechanical fatigue test until failure, with load applied to the pontic using the stepwise stress methodology (initial load of 100 N for 5000 cycles, followed by an increase to 200 N for 20 000 cycles, with a subsequent increase of 50 N each step). For data analysis, fatigue failure load (FFL) and cycles for fatigue failure (CFF) were recorded. Failed structures were analyzed by fractography. The Kaplan-Meier test followed by a log-rank Mantel-Cox post hoc test was used to analyze FFL and CFF (α=.05). Weibull analysis was also performed. RESULTS: The round (1065 N) and trapezoid (1010 N) groups presented higher FFL values than the square one (870 N) (P≤.05). For CFF, the round connector (358 777) was better than the square (280 310) (P=.006), and the trapezoid (337 773) was statistically similar to both (P>.05). No difference among groups was observed in Weibull modulus either for CFF or FFL data. All failures were catastrophic, originating at the base of the connector and propagating toward the occlusal surface of the pontic (region under loading). CONCLUSIONS: The connector cross-sectional geometry significantly influenced the mechanical fatigue performance of implant-supported fixed partial prostheses made of monolithic zirconia.

Antitubercular Activity of Novel 2-(Quinoline-4-yloxy)acetamides with Improved Drug-Like Properties.

Using cycloalkyl and electron-donating groups to decrease the carbonyl electrophilicity, a novel series of 2-(quinoline-4-yloxy)acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure-activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted the cytochrome bc 1 complex. In addition, selected molecules inhibited Mtb growth in a macrophage model of tuberculosis infection. Furthermore, the leading compound was chemically stable depending on the context and showed good kinetic solubility, high permeability, and a low rate of in vitro metabolism. Finally, the pharmacokinetic profile of the compound was assessed after oral administration to mice. To the best of our knowledge, for the first time, a 2-(quinoline-4-yloxy)acetamide was obtained with a sufficient exposure, which may enable in vivo effectiveness and its further development as an antituberculosis drug candidate.