Identification of sensitizing diethyleneglycol maleate in a two-component polyester cement

Unsaturated polyester (UP) cement caused allergic contact dermatitis in car repair work. The resin was a condensate of polyols and maleic anhydride with reactive solvent, auxiliary substances, and inorganic reinforcement substances. To identify the causative chemicals, the cement was tested on a sensitized patient. For analysis, samples of the resin were eluted with acetone and eluted with hexane to precipitate inorganic material and large polyester molecules. The eluate was evaporated. The remainder, dissolved in acetone, was separated into fractions on silica plates by thin layer chromatography (TLC). On the developed (hexane/chloroform, 15/85) plates, 20 bands were obtained under UV-light at 254 nm. Samples of the bands were scraped and used for patch testing. The scraping at a retention factor (Rf) of 0.24 caused a skin reaction. The bands at this retention were removed from six plates, combined, eluted with acetone and purified again by TLC. The purified fraction mixed in petrolatum in the dilution series was used for conclusive patch testing on the patient. An allergic reaction was induced at down to 0.003% wt/wt. According to MS and IR analyses, the isolated compound was diethyleneglycol maleate (DEGM, MW204). In addition to the resin part, the sanding dust also contained this monomer.     

Beclin 1 interactome controls the crosstalk between apoptosis,autophagy and inflammasome activation: Impact on the aging process

Autophagy and apoptosis are crucial cellular housekeeping and tissue survival mechanisms. There is emerging evidence of important crosstalk between apoptosis and autophagy which can be linked to inflammasome activation. Beclin 1 is a platform protein which assembles an interactome consisting of diverse proteins which control the initiation of autophagocytosis and distinct phases in endocytosis. Recent studies have demonstrated that the anti-apoptotic Bcl-2 family members can interact with Beclin 1 and inhibit autophagy. Consequently, impaired autophagy can trigger inflammasome activation. Interestingly, the hallmarks of the ageing process include a decline in autophagy, increased resistance to apoptosis and a low-grade inflammatory phenotype. Age-related stresses, e.g. genotoxic, metabolic and environmental insults, enhance the expression of NF-κB-driven anti-apoptotic Bcl-2 proteins which repress the Beclin 1-dependent autophagy. Suppression of autophagocytosis provokes inflammation including NF-κB activation which further potentiates anti-apoptotic defence. In a context-dependent manner, this feedback defence mechanism can enhance the aging process or provoke tumorigenesis or cellular senescence. We will review the role of Beclin 1 interactome in the crosstalk between apoptosis, autophagy and inflammasomes emphasizing that disturbances in Beclin 1-dependent autophagy can have a crucial impact on the aging process.     

Low serum magnesium levels are associated with increased risk of fractures: a long-term prospective cohort study

Magnesium, which is an essential trace element that plays a key role in several cellular processes, is a major component of bone; however, its relationship with risk of major bone fractures is uncertain. We aimed to investigate the association of baseline serum magnesium concentrations with risk of incident fractures. We analyzed data on 2245 men aged 42–61 years in the Kuopio Ischemic Heart Disease prospective cohort study, with the assessment of serum magnesium measurements and dietary intakes made at baseline. Hazard ratios [95% confidence intervals (CI)] for incident total (femoral, humeral, and forearm) and femoral fractures were assessed. During a median follow-up of 25.6 years, 123 total fractures were recorded. Serum magnesium was non-linearly associated with risk of total fractures. In age-adjusted Cox regression analysis, the hazard ratio (HR) (95% CIs) for total fractures in a comparison of the bottom quartile versus top quartile of magnesium concentrations was 2.10 (1.30–3.41), which persisted on adjustment for several established risk factors 1.99 (1.23–3.24). The association remained consistent on further adjustment for renal function, socioeconomic status, total energy intake, and several trace elements 1.80 (1.10–2.94). The corresponding adjusted HRs for femoral fractures were 2.56 (1.38–4.76), 2.43 (1.30–4.53) and 2.13 (1.13–3.99) respectively. There was no evidence of an association of dietary magnesium intake with risk of any fractures. In middle-aged Caucasian men, low serum magnesium is strongly and independently associated with an increased risk of fractures. Further research is needed to assess the potential relevance of serum magnesium in the prevention of fractures.     

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims

Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility.

Materials and Methods

The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50–75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures.

Results

Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8–5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5–9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05–2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03–2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11–4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16–3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02–2∙33, p = 0∙04).

Conclusions

Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.     

Metabolic Regulation of Cytoplasmic DNA Synthesis

The regulation of cytoplasmic DNA synthesis by the metabolites ATP and citrate has been demonstrated. Other ribonucleoside and deoxyribonucleoside triphosphates as well as α,β-methylene- and β,γ-methylene-ATP and α,β-methylene-ADP are able to partially substitute for ATP in stimulating the rate of DNA synthesis with the cytoplasmic DNA polymerase (DNA nucleotidyltransferase, EC 2.7.7.7) from bone marrow. The fact that the methylene analogs of ATP and ADP are effective in stimulating DNA synthesis indicates that the mechanism of stimulation does not involve ATP hydrolysis.     

Leptin and high-sensitivity C-reactive protein and their interaction in the metabolic syndrome in middle-aged subjects

High-sensitivity C-reactive protein (hsCRP) and leptin, known to interact at the molecular level, have been associated with the metabolic syndrome (MS). We examined the independent and joint effects of high leptin and hsCRP levels on the development of MS in a population-based cohort of middle-aged subjects (N = 1035). Leptin and hsCRP levels increased with an increase in the number of metabolic abnormalities (P < .001). However, additional adjustment for body mass index diluted the association of leptin with MS in women. In men, the association of high leptin with insulin resistance and waist circumference (P < .001), and in women, the association of high hsCRP with insulin resistance (P = .029) and waist circumference (P = .009) persisted in the multivariate logistic regression models. High leptin in men and high hsCRP in women were significant predictors of MS in logistic regression analysis (P < .001). The highest prevalence of MS (86% in men and 71% in women) was observed in the subjects who belonged to the highest quartile in both leptin and hsCRP. MS is associated independently with high leptin in men and with hsCRP in women, whereas individuals with both of these markers belong to the highest risk of metabolic cluster. The study suggests sex-specific interplay between metabolic and inflammatory markers in the pathogenesis of MS.     

Inflammaging: disturbed interplay between autophagy and inflammasomes

Inflammaging refers to a low-grade pro-inflammatory phenotype which accompanies aging in mammals. The aging process is associated with a decline in autophagic capacity which impairs cellular housekeeping, leading to protein aggregation and accumulation of dysfunctional mitochondria which provoke reactive oxygen species (ROS) production and oxidative stress. Recent studies have clearly indicated that the ROS production induced by damaged mitochondria can stimulate intracellular danger-sensing multiprotein platforms called inflammasomes. Nod-like receptor 3 (NLRP3) can be activated by many danger signals, e.g. ROS, cathepsin B released from destabilized lysosomes and aggregated proteins, all of which evoke cellular stress and are involved in the aging process. NLRP3 activation is also enhanced in many age-related diseases, e.g. atherosclerosis, obesity and type 2 diabetes. NLRP3 activates inflammatory caspases, mostly caspase-1, which cleave the inactive precursors of IL-1β and IL-18 and stimulate their secretion. Consequently, these cytokines provoke inflammatory responses and accelerate the aging process by inhibiting autophagy. In conclusion, inhibition of autophagic capacity with aging generates the inflammaging condition via the activation of inflammasomes, in particular NLRP3. We will provide here a perspective on the current research of the ROS-dependent activation of inflammasomes triggered by the decline in autophagic cleansing of dysfunctional mitochondria.