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Despite the availability of vaccines and antiviral therapies, seasonal influenza infections cause 400,000 human deaths on average per year. Low vaccine coverage and the occurrence of drug-resistant viral strains highlight the need for new and improved countermeasures. While influenza A virus (IAV) engineered to express a reporter gene may serve as a valuable tool for real-time tracking of viral infection, reporter gene insertion into IAV typically attenuates viral pathogenicity, hindering its application to research. Here, we demonstrate that lethal or even sublethal doses of bioluminescent IAV carrying the NanoLuc gene in the C-terminus of PB2 can be tracked in real-time in live mice without compromising pathogenicity. Real-time tracking of this bioluminescent IAV enables spatiotemporal viral replication tracking in animals that will facilitate the development of countermeasures by enhancing the interpretation of clinical signs and prognosis while also allowing less animal usage.

Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.

Introduction: Glossodynia (burning mouth syndrome, stomatopyrosis, orodynia) is mostly considered to be a psychosomatic disorder characterised by painful sensations within the oral cavity, particularly the tongue, without detectable abnormalities of the mucous membranes or underlying medical disorder. Frequently, patients also complain of xerostomia and dysgeusia. Based on the similar characteristics of glossodynia and neuropathic pain, comparable therapeutic approaches are recommended. Antidepressants have been the therapy of choice to date. These often lead to dry mouth and aggravation of symptoms due to their anticholinergic side-effect profile, and thus to patient incompliance. Gabapentin has been used in the treatment of neuropathic pain for some time now. Side effects and interactions are low. In particular, there are no anticholinergic mechanisms of side effects. Patients and Methods: We treated 4 female glossodynia patients with gabapentin. Results: The intensity of the typical glossodynia symptoms before start of therapy was 4.9 ± 1.1 on the Visual Analog Scale (VAS). Gabapentin therapy (900–2,400 mg/d) decreased the intensity of glossodynia symptoms in all patients to 1.3 ± 0.2. The time to the maximum and stable gabapentin effect ranged from 7 to 21 days. Discussion: Our results show a good gabapentin effect in all treated patients with glossodynia. Gabapentin is thus a very promising therapeutic approach in the treatment of glossodynia. Thanks to the rapid onset of action with only mild side effects and minimal interactions, gabapentin is probably superior to the antidepressants favoured thus far in therapy.

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