Persistence of DNMT3A mutations at long‐term remission in adult patients with AML

Mutations in DNMT3A, the gene encoding DNA methyltransferase 3 alpha, have been identified as molecular drivers in acute myeloid leukaemia (AML) with possible implications for minimal residual disease monitoring and prognosis. To further explore the utility of DNMT3A mutations as biomarkers for AML, we developed assays for sensitive detection of recurrent mutations affecting residue R882. Analysis of DNA from 298 diagnostic AML samples revealed DNMT3A mutations in 45 cases (15%), which coincided with mutations in NPM1, FLT3 and IDH1. DNMT3A mutations were stable in 12 of 13 patients presenting with relapse or secondary myelodysplastic syndrome, but were also present in remission samples from 14 patients (at allele frequencies of <1–50%) up to 8 years after initial AML diagnosis, despite the loss of all other molecular AML markers. The mutant DNMT3A allele burden was not related to the clinical course of disease. Cell sorting demonstrated the presence of DNMT3A mutations in leukaemic blasts, but also at lower allele frequencies in T and B‐cells from the same patients. Our data are consistent with the recent finding of preleukaemic stem cells in AML, which are resistant to chemotherapy. The persistence of DNMT3A mutations during remission may have important implications for the management of AML.     

Effect of AndoSan(™) on expression of adhesion molecules and production of reactive oxygen species in human monocytes and granulocytes in vivo

Abstract Background. Oral intake (60 ml daily) over 12 days in eight healthy volunteers of an immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM (AndoSan(?))), reduced the monocyte and granulocyte release of mainly proinflammatory cytokines in vivo, suggesting an anti-inflammatory effect. In this foremost in vivo study, the aim was to examine the effect of such AndoSan(?) consumption on the expression of adhesion molecules CD11b, CD11c and CD62L and production of reactive oxygen species (ROS) in leukocytes. Methodology/Principal findings. As shown by flow cytometry, there was a significant increase of CD62L expression on monocytes and granulocytes from before (day 0) compared with 12 days after daily AndoSan(?) consumption. However, only minor alterations and no clear trend in the expression of CD11b and CD11c were detected. Intracellular ROS (mainly superoxide ion) were significantly reduced in these cells from days 0 to 12. Conclusions/Significance. These results support that oral intake of AndoSan(?) exhibits an anti-inflammatory effect in humans in vivo.     

New diagnostics of the dentition on panoramic radiographs—Focusing on the peripheral nervous system as an important aetiological factor behind dental anomalies

The present review article is a summary of several previously published articles focusing on the aetiology behind deviations in the dental development such as malformation, agenesis, eruption deviations and abnormal resorption. The previous findings have not been compiled before and are documented in a series of new cases in this article. The evaluation of aetiology is based on histological knowledge about early dental development and new knowledge about the periodontal membrane. The article describes the different deviations in the dentition based on an analysis of ectodermal mucosa, innervation and ectomesenchyme. Focus is on the developmental fields in the jaws, determined by the course of the peripheral nerves.The article documents that the innervation of the jaws and teeth is an important aetiological factor behind deviations in dental development and dental eruption. The association of deviations in teeth with deviations in skin is also documented and demonstrated in agenesis, dental malformations and eruption deviations. Furthermore, the interrelationship between findings in the primary and permanent dentitions is described, specifically in resorption.The analysis distinguishes between deviations in a limited field and deviations occurring generally in the dentition. Furthermore, the bilateral occurrence of deviations in contralateral fields is described.Conclusively, the article presents advice regarding conditions that should be included in aetiology-based diagnostics.     

Addition of zinc methacrylate in dental polymers: MMP-2 inhibition and ultimate tensile strength evaluation

This study evaluated the effect of zinc methacrylate (ZM) on the inhibition of matrix metalloproteinase 2 (MMP-2) and the ultimate tensile strength (UTS) of an experimental polymer. Enzymes secreted from mouse gingival tissues were analyzed by gelatin zymography in buffers containing 5 mM CaCl₂ (Tris–CaCl₂) in 50 mM Tris–HCl buffer with various concentrations of ZM (0.5, 1, 2, 4, 8, and 16 mM). The matrix metalloproteinases present in the conditioned media were characterized by immunoprecipitation. The polymer UTS evaluation was performed in eight groups with various concentrations of ZM (0, 0.5, 1, 2.5, 5, 10, 20, and 30 wt.%), in a mechanical testing machine. MMP-2 (62 kDa) was detected in the zymographic assays and inhibited by ZM in all tested concentrations. UTS data were submitted to one-way ANOVA and Tukey's test (α = 0.05), and no significant differences were observed among groups, except in the polymer containing 30% ZM, presenting a significantly lower value when compared with the control group (p < 0.05). The results suggest that ZM inhibits MMP-2 expression in all concentrations tested, while small concentrations did not affect the ultimate tensile strength of the polymer. Zinc methacrylate is a metalloproteinase inhibitor that can be copolymerized with other methacrylate monomers. Yet, the addition of ZM did not affect the resin bond strength. Thus, in vivo tests should be performed to evaluate the performance of this material.     

Does early intensive multifactorial treatment reduce total cardiovascular burden in individuals with screen‐detected diabetes? Findings from the ADDITION‐Europe cluster‐randomized trial

Aims To describe the total cardiovascular burden (cardiovascular morbidity or mortality, revascularization or non‐traumatic amputation) in individuals with screen‐detected diabetes in the ADDITION‐Europe trial and to quantify the impact of the intervention on multiple cardiovascular events over 5 years. Methods In a pragmatic, cluster‐randomized, parallel‐group trial in four centres (Denmark; Cambridge, UK; the Netherlands; and Leicester, UK), 343 general practices were randomized to screening plus routine care (n = 1379 patients), or screening and promotion of target‐driven, intensive treatment of multiple risk factors (n = 1678). We estimated the effect of the intervention on multiple cardiovascular events after diagnosis of diabetes using the Wei, Lin and Weissfeld method. Results Over 5.3 years, 167 individuals had exactly one cardiovascular event, 53 exactly two events, and 18 three or more events. The incidence rates (95% CI) of first events and any event per 1000 person‐years were 14.6 (12.8–16.6) and 20.4 (18.2–22.6), respectively. There were non‐significant reductions in the risk of a first (hazard ratio 0.83, 95% CI 0.65–1.05) and second primary endpoint (hazard ratio 0.70, 95% CI 0.43–1.12). The overall average hazard ratio for any event was 0.77 (95% CI 0.58–1.02). Conclusions Early intensive multifactorial treatment was not associated with a significant reduction in total cardiovascular burden at 5 years. Focusing on first events in cardiovascular disease prevention trials underestimates the total cardiovascular burden to patients and the health service.     

Genetic analysis of the IL8 gene polymorphism (rs4073) in generalized aggressive periodontitis

ObjectivesInterleukin (IL)-8 is an important chemokine for regulation of the inflammatory response. A single nucleotide polymorphism (SNP) reference sequence (rs) 4073 in the IL8 gene has been shown to regulate IL-8 levels after stimulation with lipopolysaccharide. This study investigates the transmission pattern of the IL8 rs4073 risk allele A and its association with susceptibility to aggressive periodontitis (AgP) in families and in a case–control cohort of unrelated individuals from a Brazilian population.DesignGenotyping was performed by standard polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP) in 13 nuclear families and 184 unrelated subjects. Statistical analysis was performed using the transmission disequilibrium test (TDT) for the family dataset and Chi-square test and multivariate logistic regression modelling for the case–control dataset.ResultsTDT analyses did not detect evidence of over transmission of IL8 rs4073 alleles in affected and unaffected family members (allele T: 52%; allele A: 48%; p = 0.2252). How expected, analyses of cases and unrelated controls showed a significant and inverse association of age with AgP; however, a lack of association between genotypes, ethnic groups and generalized AgP was observed.ConclusionsThe SNP (rs4073) was not associated with AgP in unrelated individuals and there is no evidence of over transmission of the alleles in families with AgP, from Brazilian individuals.     

A premaxilla with a supernumerary tooth indicating a developmental region with a variety of dental abnormalities: a report of nine cases

The aim of this study was to elucidate whether a premaxilla with a supernumerary tooth has additional dental abnormalities. The study does not include premaxillas with a mesiodens, only premaxillas with parasagittally located supernumerary teeth. Radiographs from eight children, followed from 1 year and 5 months to 11 years and 5 months in the municipal dental health service in Denmark, were analyzed. One patient was seen only once. Dental abnormalities recorded included: invaginations on permanent incisors, resorption of roots of incisors, curved roots of incisors, delayed eruption, and delayed formation of roots. The study shows that there are dental abnormalities within the premaxillary region where the supernumerary tooth is located. This indicates that, apart from the supernumerary tooth, a more widespread deviation from normal conditions including tooth malformation, arrested eruption, and root resorption occur within the premaxillary region. The most important outcome of this study is that in the region with a supernumerary tooth the adjacent incisor shows delayed eruption after surgical removal of the supernumerary tooth. The deviations in root morphology, including root resorption, are not limited to patients who have had orthodontic treatment, but patients who did not receive orthodontic treatment also revealed deviations in root morphology. Therefore the treatment outcome can be different from the expected outcome.