Search

The United States is currently undergoing a major opioid crisis that has recently started to decrease its population's life expectancy due to over-mortality of its young citizens by drug overdose. Among the listed causes, physician narcotic prescriptions for both acute and chronic medical conditions are often pointed out as the main culprit for this crisis. We investigated the differences between discharge prescriptions following outpatient lumbar spine surgery between a French and a US spine surgery department. Multicenter comparative observational study. A total of 100 age and sex-matched patients: 50 patients in the American center, 50 in the French center. Amount of narcotics in MED (morphine equivalent dose) in the discharge prescription. Number of postoperative visits to the emergency room for inadequate pain control. Demographics, comorbidities, operative data, current prescriptions and discharge prescriptions were compared between the two groups. Narcotic consumption was converted in milligrams of morphine equivalent dose (mg MED). A total of 25 American patients (50%) consumed narcotics preoperatively vs 4 French patients (8%). Only 22% of Americans were opioid naïve. Postoperatively, all French patients had a narcotic-free prescription while all American patients were prescribed a significant amount of narcotics (617.04mg ± 345.16mg MED). One American patient returned to the emergency department for inadequate pain control while none of the French did. French patients were never prescribed steroids but had systematic nonsteroid inflammatory drugs while 41.4% of American patients were prescribed postoperative steroid tapers following a postoperative telephone call. For identical surgeries, all American patients were prescribed postoperative narcotics while none of the French were. Cultural beliefs from both patients, physicians and the industry probably represent the most significant barrier against the implementation of a narcotic-free culture in our practice. Reducing narcotic prescriptions in our practice is not only feasible but also highly desirable. This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation, and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feedforward circuit whereby HAT1 captures acetyl groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types. • HAT1 is an EGF-stimulated acetyltransferase required for EGF-dependent growth • HAT1 holoenzyme specifically binds to histone H4 promoters • Histone H4 promoters contain an acetate-sensitive genomic element • HAT1 expression is associated with poor cancer outcomes in humans and mice Nascent histone H4 is acetylated by cytoplasmic histone acetyltransferase 1 (HAT1) and then de-acetylated after chromatin insertion, releasing free acetate. Gruber et al. discover that HAT1 also binds an acetate-sensitive promoter element in histone H4 genes. Therefore, histone production and acetylation are linked by HAT1 to drive cell division via acetyl-Co-A regeneration. [ABSTRACT FROM AUTHOR]

Intronic microRNAs have been proposed to complicate the design and interpretation of mouse knockout studies. The endothelial-expressed Egfl7/miR-126 locus contains miR-126 within Egfl7 intron 7, and angiogenesis deficits have been previously ascribed to Egfl7 gene-trap and lacZ knock-in mice. Surprisingly, selectively floxed Egfl7Δ and miR-126Δ alleles revealed that Egfl7Δ/Δ mice were phenotypically normal, whereas miR-126Δ/Δ mice bearing a 289-nt microdeletion recapitulated previously described Egfl7 embryonic and postnatal retinal vascular phenotypes. Regulation of angiogenesis by miR-126 was confirmed by endothelial-specific deletion and in the adult cornea micropocket assay. Furthermore, miR-126 deletion inhibited VEGF-dependent Akt and Erk signaling by derepression of the p85β subunit of PI3 kinase and of Spred1, respectively. These studies demonstrate the regulation of angiogenesis by an endothelial miRNA, attribute previously described Egfl7 vascular phenotypes to miR-126, and document inadvertent miRNA dysregulation as a complication of mouse knockout strategies. [ABSTRACT FROM AUTHOR]

The activation of the blastocyst, a process by which it gains competency to attach with the receptive uterus, is a prerequisite for successful implantation. However, the molecular basis of blastocyst activation remains largely unexplored. Combining molecular, pharmacological and physiological approaches, we show here that silencing of Wnt-β-catenin signaling in mice does not adversely affect the development of preimplantation embryos to blastocysts and uterine preparation for receptivity, but, remarkably, blocks blastocyst competency to implantation. Using the physiologically relevant delayed implantation model and trophoblast stem cells in culture, we further demonstrate that a coordinated activation of canonical Wnt-β-catenin signaling with attenuation of the non-canonical Wnt-RhoA signaling pathway ensures blastocyst competency to implantation. These findings constitute novel evidence that Wnt signaling is at least one pathway that determines blastocyst competency for implantation. [ABSTRACT FROM AUTHOR]