Sap and Sun: A Case of Phytophotodermatitis.

We report a case of phytophotodermatitis caused by cow parsnip (Heracleum maximum) exposure affecting a hiker in Colorado. Phytophotodermatitis is a phototoxic skin reaction to UV-A rays after contact with photosensitizing plant substances that presents as a burning, painful rash, often with blisters. Treatment is supportive, including wound hygiene, analgesia, and anti-inflammatories. Avoiding offending plants, protecting the skin from sun, and immediate washing with soap and water after plant contact are the primary means of prevention. We have included a table and photos of plants found in the United States that can cause phytophotodermatitis. Medical providers should include phytophotodermatitis in the differential diagnosis of blistering rashes in patients who have been outdoors with possible exposure to offending plants.

microRNA let-7i-5p mediates the relationship between muscle fat infiltration and neck pain disability following motor vehicle collision: a preliminary study.

Persistent neck-pain disability (PNPD) is common following traumatic stress exposures such as motor vehicle collision (MVC). Substantial literature indicates that fat infiltration into neck muscle (MFI) is associated with post-MVC PNPD. However, little is known about the molecular mediators underlying this association. In the current study, we assessed whether microRNA expression signatures predict PNPD and whether microRNA mediate the relationship between neck MFI and PNPD. A nested cohort of 43 individuals from a longitudinal study of MVC survivors, who provided blood (PAXgene RNA) and underwent magnetic resonance imaging (MRI), were included in the current study. Peritraumatic microRNA expression levels were quantified via small RNA sequencing, neck MFI via MRI, and PNPD via the Neck Disability Index two-weeks, three-months, and twelve-months following MVC. Repeated measures regression models were used to assess the relationship between microRNA and PNPD and to perform mediation analyses. Seventeen microRNA predicted PNPD following MVC. One microRNA, let-7i-5p, mediated the relationship between neck MFI and PNPD. Peritraumatic blood-based microRNA expression levels predict PNPD following MVC and let-7i-5p might contribute to the underlying effects of neck MFI on persistent disability. In conclusion, additional studies are needed to validate this finding.

MicroRNA-19b predicts widespread pain and posttraumatic stress symptom risk in a sex-dependent manner following trauma exposure.

Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent comorbid sequelae of trauma that occur at different rates in women and men. We sought to identify microRNA (miRNA) that may contribute to sex-dependent differences in vulnerability to these outcomes. Monte Carlo simulations (x10,000) identified miRNA in which predicted targeting of PTWP or PTSS genes was most enriched. Expression of the leading candidate miRNA to target PTWP/PTSS-related genes, miR-19b, has been shown to be influenced by estrogen and stress exposure. We evaluated whether peritraumatic miR-19b blood expression levels predicted PTWP and PTSS development in women and men experiencing trauma of motor vehicle collision (n = 179) and in women experiencing sexual assault trauma (n = 74). A sex-dependent relationship was observed between miR-19b expression levels and both PTWP (ß = -2.41, P = 0.034) and PTSS (ß = -3.01, P = 0.008) development 6 months after motor vehicle collision. The relationship between miR-19b and PTSS (but not PTWP) was validated in sexual assault survivors (ß = -0.91, P = 0.013). Sex-dependent expression of miR-19b was also observed in blood and nervous tissue from 2 relevant animal models. Furthermore, in support of increasing evidence indicating a role for the circadian rhythm (CR) in PTWP and PTSS pathogenesis, miR-19b targets were enriched in CR gene transcripts. Human cohort and in vitro analyses assessing miR-19b regulation of key CR transcripts, CLOCK and RORA, supported the potential importance of miR-19b to regulating the CR pathway. Together, these results highlight the potential role that sex-dependent expression of miR-19b might play in PTWP and PTSS development after trauma/stress exposure.

Evaluation of the Association Between Genetic Variants in Circadian Rhythm Genes and Posttraumatic Stress Symptoms Identifies a Potential Functional Allele in the Transcription Factor TEF.

Previous studies suggest that genetic variants within genes affecting the circadian rhythm influence the development of posttraumatic stress symptoms (PTSS). In the present study, we used data from three emergency care-based cohorts to search genetic variants in circadian pathway genes previously associated with neuropsychiatric disorders for variants that influence PTSS severity. The three cohorts used included a discovery cohort of African American men and women enrolled following motor vehicle collision (n = 907) and two replication cohorts: one of multi-ethnic women enrolled following sexual assault (n = 274) and one of multi-ethnic men and women enrolled following major thermal burn injury (n = 68). DNA and RNA were collected from trauma survivors at the time of initial assessment. Validated questionnaires were used to assess peritraumatic distress severity and to assess PTSS severity 6 weeks, 6 months, and 1 year following trauma exposure. Thirty-one genetic variants from circadian rhythm genes were selected for analyses, and main effect and potential gene*stress and gene*sex interactions were evaluated. Secondary analyses assessed whether associated genetic variants affected mRNA expression levels. We found that six genetic variants across five circadian rhythm-associated genes predicted PTSS outcomes following motor vehicle collision (p < 0.05), but only two of these variants survived adjustment for multiple comparisons (False Discovery Rate < 5%). The strongest of these associations, an interaction between the PAR-zip transcription factor, thyrotroph embryonic factor (TEF) variant rs5758324 and peritraumatic distress, predicted PTSS development in all three cohorts. Further analysis of genetic variants in the genetic region surrounding TEFrs5758324 (±125,000 nucleotides) indicated that this allele showed the strongest association. Further, TEF RNA expression levels (determined via RNA-seq) were positively associated with PTSS severity in distressed individuals with at least one copy of the TEFrs5758324 minor allele. These results suggest that rs5758324 genetic variant in TEF, a regulator of clock-controlled genes and key mediator of the core circadian rhythm, influence PTSS severity in a stress-dependent manner.

A Functional riboSNitch in the 3' Untranslated Region of FKBP5 Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Post-Traumatic Pain.

Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene-miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies.SIGNIFICANCE STATEMENTFKBP5 is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of FKBP5 that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the FKBP5 rs3800373 minor allele alters the secondary structure of FKBP5 mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater FKBP5 translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.