Research Spotlight

Strack, J.E., Torres, V.A., Pennington, M.L., Cardenas, M.N., Dupree, J., Meyer, E.C., Dolan, S., Kruse, M.I., Synett, S.J., Kimbrel, N.A. and Gulliver, S.B. (2021). “Psychological distress and line-of-duty head injuries in firefighters.” Occup Med (Lond) 71(2): 99-104.

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BACKGROUND: Head injuries are common injury in the fire service; however, very little data exist on the risks this may pose to the development of post-traumatic stress disorder (PTSD) and depression in this high-risk population. AIMS: Our study aimed to compare levels of PTSD and depression symptoms in firefighters with a line-of-duty head injury, non-line-of-duty head injury and no head injury. METHODS: In this cross-sectional study, we assessed current PTSD and depression symptoms as well as retrospective head injuries. RESULTS: Seventy-six per cent of the total sample reported at least one head injury in their lifetime. Depression symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to those with no head injury, but not compared to those who sustained a non-line-of-duty head injury. Depression symptoms did not differ between firefighters with a non-line-of-duty head injury and those with no head injury. PTSD symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to both firefighters with no head injury and those with a non-line-of-duty head injury. CONCLUSIONS: We found that firefighters who reported at least one line-of-duty head injury had significantly higher levels of PTSD and depression symptoms than firefighters who reported no head injuries. Our findings also suggest head injuries sustained outside of fire service could have less of an impact on the firefighter’s PTSD symptom severity than head injuries that occur as a direct result of their job.

Odze, R., Spechler, S.J., Podgaetz, E., Nguyen, A., Konda, V. and Souza, R.F. (2021). “Histologic Study of the Esophagogastric Junction of Organ Donors Reveals Novel Glandular Structures in Normal Esophageal and Gastric Mucosae.” Clin Transl Gastroenterol 12(5): e00346.

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INTRODUCTION: Whether cardiac mucosa at the esophagogastric junction is normal or metaplastic is controversial. Studies attempting to resolve this issue have been limited by the use of superficial pinch biopsies, abnormal esophagi resected typically because of cancer, or autopsy specimens in which tissue autolysis in the stomach obscures histologic findings. METHODS: We performed histologic and immunohistochemical studies of the freshly fixed esophagus and stomach resected from 7 heart-beating, deceased organ donors with no history of esophageal or gastric disease and with minimal or no histologic evidence of esophagitis and gastritis. RESULTS: All subjects had cardiac mucosa, consisting of a mixture of mucous and oxyntic glands with surface foveolar epithelium, at the esophagogastric junction. All also had unique structures we termed compact mucous glands (CMG), which were histologically and immunohistochemically identical to the mucous glands of cardiac mucosa, under esophageal squamous epithelium and, hitherto undescribed, in uninflamed oxyntic mucosa throughout the gastric fundus. DISCUSSION: These findings support cardiac mucosa as a normal anatomic structure and do not support the hypothesis that cardiac mucosa is always metaplastic. However, they do support our novel hypothesis that in the setting of reflux esophagitis, reflux-induced damage to squamous epithelium exposes underlying CMG (which are likely more resistant to acid-peptic damage than squamous epithelium), and proliferation of these CMG as part of a wound-healing process to repair the acid-peptic damage could result in their expansion to the mucosal surface to be recognized as cardiac mucosa of a columnar-lined esophagus.

Odiase, E., Zhang, X., Chang, Y., Nelson, M., Balaji, U., Gu, J., Zhang, Q., Pan, Z., Spechler, S.J. and Souza, R.F. (2021). “In Esophageal Squamous Cells From Eosinophilic Esophagitis Patients, Th2 Cytokines Increase Eotaxin-3 Secretion Through Effects on Intracellular Calcium and a Non-Gastric Proton Pump.” Gastroenterology 160(6): 2072-2088.e2076.

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BACKGROUND & AIMS: In upper airway cells, T helper 2 cytokines that signal through interleukin-4 (IL-4) receptor-α have been shown to stimulate eotaxin-3 secretion via a nongastric proton pump (ngH(+),K(+)ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH(+),K(+)ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL-4 receptor-α signaling. METHODS: ngH(+),K(+)ATPase expression in EoE cells was evaluated by quantitative real-time polymerase chain reaction and Western blotting. IL-4-stimulated eotaxin-3 secretion was measured by enzyme-linked immunosorbent assay after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), ethylene glycol-bis(β-aminoethyl)-N,N,N’,N’-tetraacetoxymethyl ester (calcium chelator), 2-aminoethoxydiphenyl borate (inhibitor of endoplasmic reticulum calcium release), verapamil, and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of patients with EoE and controls. RESULTS: EoE cells expressed ngH(+),K(+)ATPase messenger RNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by ethylene glycol-bis(β-aminoethyl)-N,N,N’,N’-tetraacetoxymethyl ester, 2-aminoethoxydiphenyl borate, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls. CONCLUSIONS: EoE cells express a nongastric proton pump that mediates T helper 2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block T helper 2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment.

Sheth, M.A., Widmer, R.J. and Dandapantula, H.K. (2021). “Pathobiology and evolving therapies of coronary artery vasospasm.” Proc (Bayl Univ Med Cent) 34(3): 352-360.

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Coronary artery vasospasm is a known cause of chest pain and requires a high level of clinical suspicion for diagnosis. It also remains in the differential diagnosis for patients presenting with type 2 myocardial infarction. There are few randomized controlled trials for guideline-based prevention and treatment for coronary artery vasospasm. In this article, we review updated concepts in coronary artery vasospasm. Specifically, our aim is to provide current evidence of pathophysiology, identify the risk factors, propose a diagnostic algorithm, review available evidence of evolving therapies, and identify patients who would benefit from automatic implantable cardioverter defibrillators.

Wu, Y.S., Khanna, R., Schmith, V., Lun, Y., Shen, J.S., Garcia, A., Dungan, L., Perry, A., Martin, L., Tsai, P.C., Hamler, R., Das, A.M., Schiffmann, R. and Johnson, F.K. (2021). “Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.” Clin Pharmacol Drug Dev.

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Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.