SUMMARYGeneralized arterial calcification of infancy (GACI), an autosomal recessive disorder, is characterized by early mineralization of blood vessels, often diagnosed by prenatal ultrasound and usually resulting in demise during the first year of life. It is caused in most cases by mutations in the ENPP1 gene, encoding an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate, the latter being a powerful anti-mineralization factor. Recently, a novel mouse phenotype was recognized as a result of ENU mutagenesis – those mice developed stiffening of the joints, hence the mutant mouse was named ‘ages with stiffened joints’ (asj). These mice harbor a missense mutation, p.V246D, in the Enpp1 gene. Here we demonstrate that the mutant ENPP1 protein is largely absent in the liver of asj mice, and the lack of enzymatic activity results in reduced inorganic pyrophosphate (PPi) levels in the plasma, accompanied by extensive mineralization of a number of tissues, including arterial blood vessels. The progress of mineralization is highly dependent on the mineral composition of the diet, with significant shortening of the lifespan on a diet enriched in phosphorus and low in magnesium. These results suggest that the asj mouse can serve as an animal model for GACI.
Tobacco smoke (TS) is a major cause of human bladder cancer (BC). Two components in TS, 4-aminobiphenyl (4-ABP) and acrolein, which also are environmental contaminants, can cause bladder tumor in rat models. Their role in TS related BC has not been forthcoming. To establish the relationship between acrolein and 4-ABP exposure and BC, we analyzed acrolein-deoxyguanosine (dG) and 4-ABP-DNA adducts in normal human urothelial mucosa (NHUM) and bladder tumor tissues (BTT), and measured their mutagenicity in human urothelial cells. We found that the acrolein-dG levels in NHUM and BTT are 10-30 fold higher than 4-ABP-DNA adduct levels and that the acrolein-dG levels in BTT are 2 fold higher than in NHUM. Both acrolein-dG and 4-ABP-DNA adducts are mutagenic; however, the former are 5 fold more mutagenic than the latter. These two types of DNA adducts induce different mutational signatures and spectra. We found that acrolein inhibits nucleotide excision and base excision repair and induces repair protein degradation in urothelial cells. Since acrolein is abundant in TS, inhaled acrolein is excreted into urine and accumulates in the bladder and because acrolein inhibits DNA repair and acrolein-dG DNA adducts are mutagenic, we propose that acrolein is a major bladder carcinogen in TS.
Purpose; The COVID-19 pandemic has necessitated profound adaptations in the delivery of healthcare to manage a rise in critically unwell patients. In an attempt to slow the spread of the virus nationwide lockdown restrictions were introduced. This review aims to scope the literature on the impact of the pandemic and subsequent lockdown on the presentation and management of trauma globally.
Methods; A scoping review was conducted in accordance with PRISMA-ScR guidelines. A systematic search was carried out on the Medline, EMBASE and Cochrane databases to identify papers investigating presentation and management of trauma during the COVID-19 pandemic. All studies based on patients admitted with orthopaedic trauma during the COVID-19 pandemic were included. Exclusion criteria were opinion-based reports, reviews, studies that did not provide quantitative data and papers not in English.
Results; Three hundred and thirty seven studies were screened, with 17 meeting the eligibility criteria. Studies reported on the footfall of trauma in the UK, Europe, Asia, USA, Australia and New Zealand. A total of 29,591 patients during the pandemic were considered. Mean age was 43.7 years (range <1–103); 54.8% were male. Reported reductions in trauma footfall ranged from 20.3% to 84.6%, with a higher proportion of trauma occurring secondary to interpersonal violence, deliberate self-harm and falls from a height. A decrease was seen in road traffic collisions, sports injuries and trauma occurring outdoors. There was no significant change in the proportion of patients managed operatively, and the number of trauma patients reported to be COVID-19 positive was low.
Conclusion; Whilst the worldwide COVID-19 pandemic has caused a reduction in the number of trauma patients; the services managing trauma have continued to function despite infrastructural, personnel and pathway changes in health systems. The substantial effect of the COVID-19 pandemic on elective orthopaedics is well described, however the contents of this review evidence minimal change in the delivery of effective trauma care despite resource constraints during this global COVID-19 pandemic.
The addition of DISE to our preoperative workup has contributed to a decreased rate of multilevel surgery and increased rate of surgical success through identification of the individual patient's OSA architecture and customization of the surgical plan.
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