A Tale of Switched Functions: From Cyclooxygenase Inhibition to M-Channel Modulation in New Diphenylamine Derivatives

Cyclooxygenase (COX) enzymes are molecular targets of nonsteroidal anti-inflammatory drugs (NSAIDs), the most used medication worldwide. However, the COX enzymes are not the sole molecular targets of NSAIDs. Recently, we showed that two NSAIDs, diclofenac and meclofenamate, also act as openers of Kv7.2/3 K+ channels underlying the neuronal M-current. Here we designed new derivatives of diphenylamine carboxylate to dissociate the M-channel opener property from COX inhibition. The carboxylate moiety was derivatized into amides or esters and linked to various alkyl and ether chains. Powerful M-channel openers were generated, provided that the diphenylamine moiety and a terminal hydroxyl group are preserved. In transfected CHO cells, they activated recombinant Kv7.2/3 K+ channels, causing a hyperpolarizing shift of current activation as measured by whole-cell patch-clamp recording. In sensory dorsal root ganglion and hippocampal neurons, the openers hyperpolarized the membrane potential and robustly depressed evoked spike discharges. They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents. In vivo, the openers exhibited anti-convulsant activity, as measured in mice by the maximal electroshock seizure model. Conversion of the carboxylate function into amide abolished COX inhibition but preserved M-channel modulation. Remarkably, the very same template let us generating potent M-channel blockers. Our results reveal a new and crucial determinant of NSAID-mediated COX inhibition. They also provide a structural framework for designing novel M-channel modulators, including openers and blockers

FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP

Protein folding homeostasis in the endoplasmic reticulum (ER) is defended by an unfolded protein response that matches ER chaperone capacity to the burden of unfolded proteins. As levels of unfolded proteins decline, a metazoan-specific FIC-domain-containing ER-localized enzyme (FICD) rapidly inactivates the major ER chaperone BiP by AMPylating T518. Here we show that the single catalytic domain of FICD can also release the attached AMP, restoring functionality to BiP. Consistent with a role for endogenous FICD in de-AMPylating BiP, FICD$_{-/-}$ hamster cells are hypersensitive to introduction of a constitutively AMPylating, de-AMPylation-defective mutant FICD. These opposing activities hinge on a regulatory residue, E234, whose default state renders FICD a constitutive de-AMPylase $\textit{in vitro}$. The location of E234 on a conserved regulatory helix and the mutually antagonistic activities of FICD $\textit{in vivo}$, suggest a mechanism whereby fluctuating unfolded protein load actively switches FICD from a de-AMPylase to an AMPylase.Supported by Wellcome Trust Principal Research Fellowship to D.R. (Wellcome 200848/Z/16/Z), a UK Medical Research Council PhD studentship to L.A.P. and a Wellcome Trust Strategic Award to the Cambridge Institute for Medical Research (Wellcome 100140)

ICAR: endoscopic skull‐base surgery

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International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Bactericidal activities and post-antibiotic effects of ofloxacin and ceftriaxone against drug-resistant Salmonella enterica serovar Typhi

Background The clinical response to ceftriaxone in patients with typhoid fever is significantly slower than with ofloxacin, despite infection with Salmonella enterica serovar Typhi (S. Typhi) isolates with similar susceptibilities (MIC 0.03–0.12 mg/L). The response to ofloxacin is slower if the isolate has intermediate susceptibility (MIC 0.25–1.0 mg/L). Objectives To determine the bactericidal activity and post-antibiotic effect (PAE) of ceftriaxone and ofloxacin against S. Typhi. Methods The mean time to reach a 99.9% reduction in log10 count (bactericidal activity) and PAE of ceftriaxone and ofloxacin were determined for 18 clinical isolates of S. Typhi in time–kill experiments (MIC range for ofloxacin 0.06–1.0 mg/L and for ceftriaxone 0.03–0.12 mg/L). Results The mean (SD) bactericidal activity of ofloxacin was 33.1 (15.2) min and 384.4 (60) min for ceftriaxone. After a 30 min exposure to ofloxacin, the mean (SD) duration of PAE was 154.7 (52.6) min. There was no detectable PAE after 1 h of exposure to ceftriaxone. For ofloxacin, bactericidal activity and PAE did not significantly differ between isolates with full or intermediate susceptibility provided ofloxacin concentrations were maintained at 4×MIC. Conclusions Infections with S. Typhi with intermediate ofloxacin susceptibility may respond to doses that maintain ofloxacin concentrations at 4×MIC at the site of infection. The slow bactericidal activity of ceftriaxone and absent PAE may explain the slow clinical response in typhoid

Brief screening for maternal mental health in Vietnam: Measures of positive wellbeing and perceived stress predict prenatal and postnatal depression

Background: In many countries, there is limited consideration of the psychological wellbeing of women during antenatal and postnatal care. Among a range of contributing factors, one practical reason is that brief, valid and reliable screening tools are not widely used to guide clinical interviews. The present study evaluated psychometric properties of three brief scales that measure recent wellbeing (the WHO-5 index), perceived stress (the PSS-10) and depression (the PHQ-9). Methods: A prospective birth cohort study was completed in Hue City, central Vietnam with 148 pregnant women in the third trimester of pregnancy, with follow-up 3-5 months after childbirth. Moderate-to-severe antenatal depressive symptoms were used as the reference standard to validate the WHO-5 and PSS-10. Results: Approximately one-third of the women indicated significant stress and 12% reported moderate to severe depressive symptoms during pregnancy. The WHO-5 and PSS-10 had good internal consistency (Cronbach’s alpha=0.76–0.81) and good discriminant properties against prenatal depression. Area Under the Curve (AUC) values showed good predictive validity to detect postpartum depressive symptoms for the WHO-5 [AUC=0.73, 95% CI (0.60 - 0.86)] and the PSS-10 [AUC=0.69, 95% CI (0.45 – 0.92)]. WHO-5 scores ≤ 60/100 and PSS-10 scores ≥ 20/40 provided good sensitivity (approx.83%) and fair specificity (approx.61%) to detect depression pre- and post-natally. Conclusions: Given these satisfactory psychometric properties, brief but broad screening that includes questions about positive wellbeing and recent stress in addition to depressive symptoms should be integrated into routine psychosocial care for pregnant women in Vietnam and similar cultural contexts

Acute febrile myalgia in Vietnam due to trichinellosis following the consumption of raw pork.

Trichinellosis outbreaks occur occasionally in Vietnam following the consumption of undercooked pork. Diagnosing trichinella can be problematic because fever and myalgia are nonspecific, and diagnosis may be delayed. We describe 5 Vietnamese patients in whom trichinellosis was diagnosed after several weeks of illness