TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

One case of bloodstream infection caused by Ureaplasma urealyticum / 中国热带医学

@#Abstract: Objective To analyze a case of bloodstream infection caused by Ureaplasma urealyticum after abortion in Anxi County Hospital, so as to provide basis for the clinical diagnosis and treatment. Methods　The diagnosis of Ureaplasma urealyticum in this patient with bloodstream infection was retrospectively analyzed. The basic clinical data and laboratory diagnosis data were collected, including the characteristics of blood culture curve, Wright staining of culture medium, drug sensitivity of Mycoplasma liquid identification, colony characteristics of solid medium, and the conclusion of targeted DNA sequencing. Through the comprehensive analysis of the above data, the rapid diagnosis of this case can be realized by optimizing the detection and diagnosis process. Results　The clinical manifestations of this patient were fever of 38.5 ℃, CRP:14.85 mg/L, WBC:14.33×109/L, NET: 85.40%, PCT: 0.12 ng/mL, IL-6: 665.6 pg/mL, positive after 3 days of blood culture, no bacteria were found in Gram stain, and sand-like purple bacteria were observed after adding Wright's stain. After inoculation in blood agar, Mycoplasma solid and liquid medium, no colonies were grown in blood agar, after 48 h and 5 d. On Mycoplasma A7 agar, the edge of brown fried egg colony was striature, and it could be identified as Ureaplasma urealyticum with the Mycoplasma ID & AST panel, which was resistant to quinolones and spectinomycin, but sensitive to macrolides, tetracyclines and lincomycin. Subsequent targeted DNA sequencing results were also confirmed for Ureaplasma urealyticum. Before receiving the report, clinical experience treatment with ceftriaxone metronidazole was used to fight infection with negative bacilli and anaerobic bacteria. Mycoplasma was not treated with targeted treatment. After 3 days, the patient's body temperature returned to normal, inflammation index decreased, and the patient asked to be discharged. Conclusions　At present, there are few reports of bloodstream infection caused by Ureaplasma urealyticum, and the lack of clinical understanding can easily lead to misdiagnosis and missed diagnosis. In order to improve the detection rate of Mycoplasma in blood culture, it is necessary to optimize the detection procedure of blood culture and provide accurate diagnosis and treatment basis for clinical practice. However, it is clear from this case that Mycoplasma bloodstream infection cases are self-limited infection and can recover by themselves without targeted treatment in patients with normal immunity. Therefore, it is very important to protect the immunity of patients.