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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disabling disease with unclear etiology and pathophysiology, whose typical symptoms include prolonged debilitating recovery from fatigue or postexertional malaise (PEM). Disrupted production of adenosine triphosphate (ATP), the intracellular energy that fuels cellular activity, is a cause for fatigue. Here, we present a long-term case of ME/CFS: a 75-year-old Caucasian female patient, whose symptoms of ME/CFS were clearly triggered by an acute infection of the Epstein–Barr virus 24 years ago (mononucleosis). Before then, the patient was a healthy professional woman. A recent DNA sequence analysis identified missense variants of mitochondrial respiratory chain enzymes, including ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V). Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the Cox1 gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the ATP6 gene encodes subunit A of complex V (CV: ATP synthase). CIV and CV are the last two of five essential enzymes that perform the mitochondrial electron transport respiratory chain reaction to generate ATP. Further analysis of the blood sample using transmission electron microscopy demonstrated abnormal, circulating, extracellular mitochondria. These results indicate that the patient had dysfunctional mitochondria, which may contribute directly to her major symptoms, including PEM and neurological and cognitive changes. Furthermore, the identified variants of ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V), functioning at a later stage of mitochondrial ATP production, may play a role in the abnormality of the patient’s mitochondria and the development of her ME/CFS symptoms.

Abstract The cellular and molecular underpinnings of Wallerian degeneration have been robustly explored in laboratory models of successful nerve regeneration. In contrast, there is limited interrogation of failed regeneration, which is the challenge facing clinical practice. Specifically, we lack insight on the pathophysiologic mechanisms that lead to the formation of neuromas-in-continuity (NIC). To address this knowledge gap, we have developed and validated a novel basic science model of rapid-stretch nerve injury, which provides a biofidelic injury with NIC development and incomplete neurologic recovery. In this study, we applied next-generation RNA sequencing to elucidate the temporal transcriptional landscape of pathophysiologic nerve regeneration. To corroborate genetic analysis, nerves were subject to immunofluorescent staining for transcripts representative of the prominent biological pathways identified. Pathophysiologic nerve regeneration produces substantially altered genetic profiles both temporally and in the mature neuroma microenvironment, in contrast to the coordinated genetic signatures of Wallerian degeneration and successful regeneration. To our knowledge, this study presents as the first transcriptional study of NIC pathophysiology and has identified cellular death, fibrosis, neurodegeneration, metabolism, and unresolved inflammatory signatures that diverge from pathways elaborated by traditional models of successful nerve regeneration.

Pain is often debilitating, and current treatments are neither universally efficacious nor without risks. Transient receptor potential (TRP) ion channels offer alternative targets for pain relief, but little is known about the regulation or identities of endogenous TRP ligands that affect inflammation and pain. Here, transcriptomic and targeted lipidomic analysis of damaged tissue from the mouse spinal nerve ligation (SNL)-induced chronic pain model revealed a time-dependent increase in Cyp1b1 mRNA and a concurrent accumulation of 8,9-epoxyeicosatrienoic acid (EET) and 19,20-EpDPA post injury. Production of 8,9-EET and 19,20-EpDPA by human/mouse CYP1B1 was confirmed in vitro, and 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptidergic dorsal root ganglia (DRG) neurons. TRPA1 activation by 8,9-EET and 19,20-EpDPA was attenuated by the antagonist A967079, and mouse TRPA1 was more responsive to 8,9-EET and 19,20-EpDPA than human TRPA1. This latter effect mapped to residues Y933, G939, and S921 of TRPA1. Intra-plantar injection of 19,20-EpDPA induced acute mechanical, but not thermal hypersensitivity in mice, which was also blocked by A967079. Similarly, Cyp1b1-knockout mice displayed a reduced chronic pain phenotype following SNL injury. These data suggest that manipulation of the CYP1B1–oxylipin–TRPA1 axis might have therapeutic benefit.

IntroductionOne-dimensional rating scales are widely used in research and in the clinic to assess individuals’ perceptions of sensory stimuli. Although these scales provide essential knowledge of stimulus perception, their limitation to one dimension hinders our understanding of complex stimuli.MethodsTo allow improved investigation of complex stimuli, a two-dimensional scale based on the one-dimensional Gracely Box Scale was developed and tested in healthy participants on a visual and an auditory task (rating changes in brightness and size of circles and rating changes in frequency and sound pressure of sounds, which was compared to ratings on one-dimensional scales). Before performing these tasks, participants were familiarized with the intensity descriptors of the two-dimensional scale by completing two tasks. First, participants sorted the descriptors based on their judgment of the intensity of the descriptors. Second, participants evaluated the intensity of the descriptors by pressing a button for the duration they considered matching the intensity of the descriptors or squeezing a hand grip dynamometer as strong as they considered matching the intensity of the descriptors.ResultsResults from these tasks confirmed the order of the descriptors as displayed on the original rating scale. Results from the visual and auditory tasks showed that participants were able to rate changes in the physical attributes of visual or auditory stimuli on the two-dimensional scale as accurately as on one-dimensional scales.DiscussionThese results support the use of a two-dimensional scale to simultaneously report multiple dimensions of complex stimuli.