A multilocus genetic risk score for obesity: Association with BMI and metabolic alterations in a cohort with severe obesity.

Genome wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with obesity, yet effect sizes of individual SNPs are small. Therefore, the aim of our study was to investigate whether a genetic risk score (GRS) comprising risk alleles of SNPs identified in the GIANT consortium meta-analyses shows association with body mass index (BMI) and other BMI related metabolic alterations in a cohort with an extreme phenotype. Genotyping of 93 SNPs was performed in 314 obese individuals (mean BMI 40.5 ± 7.8 kg/m², aged 45 ± 12 years), participating in a standardized weight reduction program, and in 74 lean controls (mean BMI 24.6 ± 3.3 kg/m², aged 41.7 ± 13.4 years). Allele numbers of all 93 SNPs were added to a GRS. Anthropometric parameters, parameters of glucose/insulin and lipid metabolism were assessed standardized after a 12 hours fast. GRS was significantly different between controls and obese individuals (unweighted GRS: 86.6 vs 89.0, P = .002; weighted GRS: 84.9 vs 88.3, P = .005). Furthermore, linear regression analysis showed significant associations of GRS with BMI ( P < .0001), weight ( P = .0005), waist circumference ( P = .0039), fat mass ( P < .0001) and epicardial fat thickness ( P = .0032), yet with small effect sizes ( r ² < 0.06). In conclusion, in our study GRS could differentiate between extreme obese and lean individuals, and was associated with BMI and its related traits, yet with small effect sizes.

Radiographic Evaluation of First Tarsometatarsal Joint Arthrodesis for Hallux Valgus Deformity: Does the Fusion of the First to the Second Metatarsal Base Reduce the Radiological Recurrence Rate?

BACKGROUND: Modified Lapidus arthrodesis (MLA) is a well-established treatment option for symptomatic hallux valgus deformity (HVD). However, recurrence of the deformity remains a concern. The goal of this study was to evaluate the effect of an additional intermetatarsal fusion on the radiographic recurrence rate after first tarsometatarsal (TMT-I) arthrodesis. METHODS: This is a retrospective evaluation of 56 feet that underwent TMT-I arthrodesis for moderate to severe HVD. Twenty-three feet received an isolated arthrodesis of the TMT-I joint (TMT-I), whereas 33 feet received an additional fusion between the base of the first and the second metatarsal bone (TMT-I/II). Various radiological parameters were determined preoperatively, 6 weeks and at a mean of 2 years postoperatively. RESULTS: The intermetatarsal angle (IMA) and the hallux valgus angle (HVA) were significantly lowered at both follow-up evaluations in both groups. In the TMT-I/II group, the initial reduction of HVA was significantly higher (29.3° vs 21.1°). This difference disappeared by the second follow-up, leaving no significant differences between both techniques at final follow-up. Radiological recurrence rates of HVD were comparable in both groups. CONCLUSIONS: Isolated TMT-I arthrodesis provides reliable radiological results in the correction of HVD. Whether additional fusion of the first and second metatarsal base should be routinely performed remains unclear. LEVELS OF EVIDENCE: Level 3.

Predictive impact of the inflammation-based indices in uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion.

BACKGROUND: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. PATIENTS AND METHODS: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed. RESULTS: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 vs. 5.2; p = 0.0005), low SII (10.8 vs. 5.6; p = 0.0005), low NLR (11.1 vs. 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 vs. 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 vs. 5.6; p = 0.01), and tumor burden ≦ 50% (8.2 vs. 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ≦ 1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001). CONCLUSIONS: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.

The epigenetic pioneer EGR2 initiates DNA demethylation in differentiating monocytes at both stable and transient binding sites.

The differentiation of human blood monocytes (MO), the post-mitotic precursors of macrophages (MAC) and dendritic cells (moDC), is accompanied by the active turnover of DNA methylation, but the extent, consequences and mechanisms of DNA methylation changes remain unclear. Here, we profile and compare epigenetic landscapes during IL-4/GM-CSF-driven MO differentiation across the genome and detect several thousand regions that are actively demethylated during culture, both with or without accompanying changes in chromatin accessibility or transcription factor (TF) binding. We further identify TF that are globally associated with DNA demethylation processes. While interferon regulatory factor 4 (IRF4) is found to control hallmark dendritic cell functions with less impact on DNA methylation, early growth response 2 (EGR2) proves essential for MO differentiation as well as DNA methylation turnover at its binding sites. We also show that ERG2 interacts with the 5mC hydroxylase TET2, and its consensus binding sequences show a characteristic DNA methylation footprint at demethylated sites with or without detectable protein binding. Our findings reveal an essential role for EGR2 as epigenetic pioneer in human MO and suggest that active DNA demethylation can be initiated by the TET2-recruiting TF both at stable and transient binding sites.

Profiling of aberrant DNA methylation in acute myeloid leukemia reveals subclasses of CG-rich regions with epigenetic or genetic association.

Malignant transformation is frequently associated with disease-specific epigenetic alterations, but the underlying mechanisms and pathophysiological consequences remain poorly understood. Here, we used global comparative DNA methylation profiling at CG-rich regions of 27 acute myeloid leukemia (AML) samples to select a subset of aberrantly methylated CG-rich regions (~400 regions, ~15,000 CpGs) for quantitative DNA methylation profiling in a large cohort of AML patients (n = 196) using MALDI-TOF analysis of bisulfite-treated DNA. Meta-analysis separated a subgroup of CG-rich regions showing highly correlated DNA methylation changes that were marked by histone H3 lysine 27 trimethylation in normal hematopoietic progenitor cells. While the group of non-polycomb group (PcG) target regions displayed methylation patterns that correlated well with molecular and cytogenetic markers, PcG target regions displayed a much weaker association with genetic features. However, the degree of methylation gain across the latter panel showed significant correlation with active DNMT3A levels and with overall survival. Our study suggests that both epigenetic as well as genetic aberrations underlay AML-related changes in DNA methylation at CG-rich regions and that the former may provide a marker to improve classification and prognostication of adult AML patients.

Characterization of biologically available wood combustion particles in cell culture medium.

Combustion of wood produces particulate matter (PM) emissions having the potential to induce respiratory tract diseases in humans. To date, however, few, if any, in vitro submerse exposure adverse effect studies characterized the actual particle characteristics within the culture medium. Indeed, the availability of particles and adsorbed toxic compounds in liquids may depend on particle characteristics, i.e. aggregation, size, composition, type (complex solids, salts, etc.) and thus affect toxicity. Using polystyrene nanoparticles as reference, the particle size distribution and aggregation status of wood furnace PM and quartz particles in standard cell culture medium and water was characterized. Characterization was carried out via scanning electron microscopy (SEM), light microscopy, dynamic light scattering (DLS), and laser diffraction. Moreover, the biological availability of particles and adsorbed polycyclic aromatic hydrocarbons was tested using an Ah-receptor reporter gene assay, which demonstrated that particle characterization and knowledge of toxin bioavailability prior to experimentation is key for understanding potential biological interactions.