The development of craniofacial skeletal structures requires well-orchestrated tissue interactions controlled by distinct molecular signals. Disruptions in normal function of these molecular signals have been associated with a wide range of craniofacial malformations. A pathway mediated by estrogens is one of those molecular signals that plays role in formation of bone and cartilage including craniofacial skeletogenesis. Studies in zebrafish have shown that while higher concentrations of 17-β estradiol (E2) cause severe craniofacial defects, treatment with lower concentrations result in subtle changes in head morphology characterized with shorter snouts and flatter faces. The molecular basis for these morphological changes, particularly the subtle skeletal effects mediated by lower E2 concentrations, remains unexplored. In the present study we address these effects at a molecular level by quantitative expression analysis of sets of candidate genes in developing heads of zebrafish larvae treated with two different E2 concentrations. To this end, we first validated three suitable reference genes, ppia2, rpl8 and tbp, to permit sensitive quantitative real-time PCR analysis. Next, we profiled the expression of 28 skeletogenesis-associated genes that potentially respond to estrogen signals and play role in craniofacial development. We found E2 mediated differential expression of genes involved in extracellular matrix (ECM) remodelling, mmp2/9/13, sparc and timp2a, as well as components of skeletogenic pathways, bmp2a, erf, ptch1/2, rankl, rarab and sfrp1a. Furthermore, we identified a co-expressed network of genes, including cpn1, dnajc3, esr1, lman1, rrbp1a, ssr1 and tram1 with a stronger inductive response to a lower dose of E2 during larval head development.
Atrazine is a commonly used herbicide that has previously been implicated as an endocrine-disrupting compound. Previous studies have shown that estrogenic endocrine-disrupting compounds affect the development of the heart, cartilage, and bone in zebrafish ( Danio rerio). To determine whether atrazine has effects similar to other endocrine disruptors, zebrafish embryos were treated with a range of atrazine concentrations. Atrazine treatment at a low concentration of 0.1 µM resulted in significant differences in craniofacial cartilage elements, while concentrations ≥1 µM led to decreased survival and increased heart rates. Fish treated with ≥1 µM atrazine also developed with delayed vertebrae mineralization. Higher concentrations of atrazine caused gross craniofacial defects and decreased hatching rates. Further studies into the molecular pathways disrupted in these developmental processes could shed light on a link between endocrine-disrupting compounds and developmental abnormalities.
The Beers Criteria for Potentially Inappropriate Medication (PIM) use is a list of medications with multiple risks in older patients. Approximately 24 per cent use rate is reported in prior studies. Our objective was to determine the local PIM use and subsequent fall risk in geriatric trauma patients. We conducted a retrospective analysis of PIM use in all geriatric patients evaluated at our Level 1 trauma center between 2014 and 2017. Patients were identified from our trauma database. Pre-admission medication use was determined through medication reconciliation from our electronic medical record (EMR). Patients not undergoing medication reconciliation were excluded. After initial analysis, patients were stratified by age into three groups: 65 to 74, 75 to 84, and ≥85 years. Multivariate logistic regression analyses were used to calculate odds ratios of falls for specific PIMs. In all, 2181 patients met the inclusion criteria. Overall, 71.2 per cent of geriatric trauma patients were prescribed at least one PIM—73.1 per cent of falls compared with 68.6 per cent for other mechanisms. Specific PIM use varied by age group. PIMs associated with fall risk in all patients included antipsychotics, benzodiazepines, and diclofenac. For those aged 65 to 74 years, antihistamines, diclofenac, proton pump inhibitors, and promethazine were associated. In those aged 75 to 84 years, alprazolam, antipsychotics, benzodiazepines, cyclobenzaprine, diclofenac, and muscle relaxants were implicated. No significant associations were found for patients aged ≥85 years. PIM use at our trauma center seems to be rampant and well above the national average. Geriatric falls were associated with using ≥1 PIM and multiple specific PIMs implicated. We are designing a targeted educational program for local primary care physicians (PCPs) that will attempt to decrease geriatric PIM use.
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