Fipronil Affects Craniofacial and Heart Development in Zebrafish Embryos (Danio rerio).

Fipronil is a broad-spectrum insecticide that has off-target effects in developing vertebrate embryos. In this study, we investigate treatment of zebrafish embryos with fipronil over the course of 5 days and examine the effects on body length, the cardiovascular system, and craniofacial morphology. We found the insecticide caused shorter body length and a decrease in eye size. By examining specific heart chamber morphology, as well as jaw angle and length, we quantified defects including enlargement of the heart and increases in jaw length and width. Further studies are needed to assess the mechanisms of fipronil's effect on vertebrate development for both environmental and human health concerns.

The Prevalence of Beers Criteria Medication Use and Associations with Falls in Geriatric Patients at a Level 1 Trauma Center.

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.

The Beers criteria: Not just for geriatrics anymore? Analysis of Beers criteria medications in nongeriatric trauma patients and their association with falls.

BACKGROUND: It has been well established that many classes of medications on the Beers list of Potentially Inappropriate Medications (PIMs) are associated with falls and injuries in the geriatric population, but little work has been performed to understand if similar relationships exist among the nongeriatric adult population. METHODS: A retrospective chart review of 32 months of trauma encounters at our Level I trauma center was performed in nongeriatric adults aged 18 years to 64 years. Encounters were reviewed by mechanism of injury and intake medication reconciliation. The data were then evaluated for associations between PIMs and falls. RESULTS: Of the 7,897 trauma encounters in the study period, 6,493 had completed medication reconciliation, and 4,154 were between the ages of 18 years and 64 years. There was a statistically significant disproportionate number of those who sustained a fall on psychoactive medications and proton pump inhibitors, and the odds of a trauma patient presenting as a fall were also significantly higher on these select classes of PIMs. CONCLUSION: The PIMs associated with falls in the geriatric population are also associated with falls in the nongeriatric population. This study supports the judicious prescribing of these medications, as they may have risks beyond what was originally thought. LEVEL OF EVIDENCE: Prognostic, level IV.

Atrazine affects craniofacial chondrogenesis and axial skeleton mineralization in zebrafish ( Danio rerio).

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.

Investigation of the effects of estrogen on skeletal gene expression during zebrafish larval head development.

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-ß estradiol (E 2) 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 E 2 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 E 2 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 E 2 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 E 2 during larval head development.

Modulation of estrogen causes disruption of craniofacial chondrogenesis in Danio rerio.

Estrogen is a steroid hormone that is ubiquitous in vertebrates, but its role in cartilage formation has not been extensively studied. Abnormalities of craniofacial cartilage and bone account for a large portion of birth defects in the United States. Zebrafish (Danio rerio) have been used as models of human disease, and their transparency in the embryonic period affords additional advantages in studying craniofacial development. In this study, zebrafish embryos were treated with 17-ß estradiol (E2) or with an aromatase inhibitor and observed for defects in craniofacial cartilage. Concentrations of E2 greater than 2µM caused major disruptions in cartilage formation. Concentrations below 2µM caused subtle changed in cartilage morphology that were only revealed by measurement. The angles formed by cartilage elements in fish treated with 1.5 and 2µM E2 were increasingly wide, while the length of the primary anterior-posterior cartilage element in these fish decreased significantly from controls. These treatments resulted in fish with shorter, flatter faces as estrogen concentration increased. Inhibition of aromatase activity also resulted in similar craniofacial disruption indicating that careful control of estrogen signaling is required for appropriate development. Further investigation of the phenomena described in this study could lead to a better understanding of the etiology of craniofacial birth defects and endocrine disruption of cartilage formation.