Location of the AICA influences the severity but not occurrence of ISSNHL:A reappraisal using high-resolution 3 T MRI

Objective:To investigate the potential influence of anatomical variation in the anterior inferior cerebellar artery(AICA)on the occurrence and severity of idiopathic sudden sensorineural hearing loss(ISSNHL).Methods:Ninety ISSNHL patients were enrolled.The anatomical location of the AICA was exhibited using high-resolution magnetic resonance imaging(MRI),and the various AICA types classified by previously reported Chavda and Gorrie methods were analyzed.The severity of hearing loss in the ipsilateral ear among different AICA types was compared.Results:Approximately 85.6%of subjects had unilateral ISSNHL(uISSNHL),and the others had bilateral ISSNHL(bISSNHL).In the uISSNHL group,the ratios of different AICA types were similar between the ipsilateral and contralateral ears.The ratios of the different AICA types in the bISSNHL group were similar to those in the uISSNHL group.In the uISSNHL group,pure tone audiometry(PTA)thresholds at 2 kHz,4 kHz and 8 kHz of patients with Chavda type II AICA were higher than those of patients with Chavda type I and type III,with a significant difference at 4 kHz between type I and type II.There was a tendency of the PTA threshold in patients with Chavda type II or Gorrie type C to gradually increase from low to high frequency zones.Conclusion:When the AICA enters the IAC(Chavda type II)or crosses between the 7th and 8th cranial nerves(Gorrie type C),the severity and frequency of hearing impairment in ISSNHL but not the occurrence of ISSNHL will be affected.

Dexamethasone does not affect endolymphatic hydrops(EH)in patients with Meniere's disease within 24 h,and intratympanic administration of gadolinium plus dexamethasone simplifies high-quality imaging of EH using a novel protocol of 7 min

Background:Intratympanic administration of gadolinium chelate allows for a better visualization of endolymphatic hydrops(EH)using MRI than intravenous injection and was recently further improved to facilitate high-quality imaging of EH in 7 min.The aim of the present study was to simplify the intratympanic administration protocol by mixing gadolinium chelate with therapeutic dexamethasone and to evaluate the effects of this mixture on the visualization of EH in MRI.Materials and methods:In an in vitro study,the potential impact of gadolinium-diethylenetriamine pentaacetic acid(Gd-DTPA)on the stability of dexamethasone was evaluated by analyzing dynamic changes in dexamethasone with high-performance liquid chromatography(HPLC)after mixing with GdDTPA.Ten patients with definite Meniere's disease(MD)were recruited to study the potential interference of dexamethasone on MRI visualization of EH,and 49 patients with MD were recruited to evaluate the effect of intratympanic injection of Gd-DTPA mixed with dexamethasone on MRI of EH using a 3T MR machine and a novel heavily T2-weighted 3-dimensional fluid-attenuated inversion recovery reconstructed using a magnitude plus zero-filled interpolation(hT2FLAIR-MZFI)sequence.Results:The retention times and peak area of dexamethasone in HPLC were not modified by the addition of Gd-DTPA.EH grading in the cochlea and vestibule was not influenced in any ear by intratympanic injection of dexamethasone.Excellent inner ear images were obtained from all patients,and EHs with various grades were displayed.There were significant correlations between diagnosis and cochlear EH(p<0.01,Spearman's Rho),between diagnosis and vestibular EH(p<0.01,Spearman's Rho),and between cochlear and vestibular EH(p<0.01,Spearman's Rho).The distribution of Gd-DTPA plus dexamethasone negatively correlated with the grade of vestibular EH.Injury of the endolymph-perilymph barrier was detected in one cochlea and three vestibules of 59 inner ears with MD.Conclusions:Intratympanic administration of Gd-DTPA plus dexamethasone yielded high-quality MRI images of EH in patients with MD using a novel 7-min protocol and simplified the clinical application.Intratympanic administration of Gd-DTPA plus dexamethasone might be used to test its therapeutic effect in future work.

MEFV,IRF8,ADA,PEPD,and NBAS gene variants and elevated serum cytokines in a patient with unilateral sporadic Meniere's disease and vascular congestion over the endolymphatic sac

The etiology and underlying mechanism of Meniere's disease(MD)development are still unknown,although inflammation and autoimmunity have been implicated as underlying mechanisms.The human endolymphatic sac(ES)has been reported to have innate and adaptive immune capacity in local immune reactions.In vivo demonstration of inflammation of the ES in patients with MD is missing in the literature.We report the case of a 47-year-old female patient diagnosed with unilateral MD with genetic variants and cytokine markers indicating inflammation and vascular congestion of the ES.Endolymphatic hydrops in the right cochlea(grade 2)and vestibulum(grade 3)were detected using MRI.She carried heterozygous variants in MEFV(c.442G>C),IRF8(c.1157G>T),ADA(c.445C>T),PEPD(c.151G>A),NBAS(c.4049T>C),CSF2RB(c.2222C>T),HPS6(c.277G>T),IL2RB(c.1109C>T),IL12RB1(c.1384G>T),IL17RC(c.260_271del GCAAGAGC TGGG),LIG1(c.746G>A),RAG1(c.650C>A),and SLX4(c.1258G>C,c.5072A>G).In the serum,the levels of granulocyte colony-stimulating factor(G-CSF),macrophage inflammatory protein 1a,and IL7 were significantly elevated,and the level of IL2Ra was reduced.Intratympanic administration of dexamethasone temporarily alleviated her hearing loss.Her vertigo was significantly relieved but remained slight after ES administration of corticosteroids.

Ferroptosis contributes to JEV-induced neuronal damage and neuroinflammation

Ferroptosis is a newly discovered prototype of programmed cell death (PCD) driven by iron-dependent phospholipid peroxidation accumulation, and it has been linked to numerous organ injuries and degenerative pathologies. Although studies have shown that a variety of cell death processes contribute to JEV-induced neuroinflammation and neuronal injury, there is currently limited research on the specific involvement of ferroptosis. In this study, we explored the neuronal ferroptosis induced by JEV infection in vitro and in vivo. Our results indicated that JEV infection induces neuronal ferroptosis through inhibiting the function of the antioxidant system mediated by glutathione (GSH)/glutathione peroxidase 4 (GPX4), as well as by promoting lipid peroxidation mediated by yes-associated protein 1 (YAP1)/long-chain acyl-CoA synthetase 4 (ACSL4). Further analyses revealed that JEV E and prM proteins function as agonists, inducing ferroptosis. Moreover, we found that treatment with a ferroptosis inhibitor in JEV-infected mice reduces the viral titers and inflammation in the mouse brains, ultimately improving the survival rate of infected mice. In conclusion, our study unveils a critical role of ferroptosis in the pathogenesis of JEV, providing new ideas for the prevention and treatment of viral encephalitis.

Screening a neurotransmitter-receptor-related inhibitor library identifies clomipramine HCl as a potential antiviral compound against Japanese encephalitis virus

Background Japanese encephalitis virus(JEV)is a leading cause of viral encephalitis worldwide.JEV exhibits significant neuroinvasiveness and neurotoxicity,resulting in considerable damage to the nervous system.Japanese encephalitis is associated with high morbidity and mortality rate,seriously harming both human health and livestock production.The current lack of specific antiviral drugs means that the development of new therapeutic agents for JEV has become urgent.Methods Anti-JEV drugs were screened from 111 inhibitors of neurotransmitter receptor-related molecules by high content technology.The antiviral effects of clomipramine HCl were evaluated through plaque assay,real-time quantitative PCR,immunofluorescence assay and western blotting assay.Bioinformatic tools were utilized to cluster the altered signaling pathway members after clomipramine HCl treatment.Finally,the anti-JEV mechanism was deeply resolved in vivo via such molecular biology and virological detection techniques.Results In this study,we screened nine compounds with significant anti-JEV activity,of which clomipramine HCl demonstrated the most potent antiviral effect and exhibited dose-dependent activity.Mechanistically,clomipramine HCl may activate endoplasmic reticulum stress and modulate the unfolded protein response,thus inhibiting the assembly stage of JEV infection.Conclusion This study highlights the importance of clomipramine HCl as a promising approach for JEV infection protection,which may lead to new host-directed antiviral approaches to such mosquito-borne viruses.

Japanese Encephalitis Virus NS1' Protein Antagonizes Interferon Beta Production

Japanese encephalitis virus(JEV) is a mosquito-borne virus and the major cause of viral encephalitis in Asia. NS1', a52-amino acid C-terminal extension of NS1, is generated with a-1 programmed ribosomal frameshift and is only present in members of the Japanese encephalitis serogroup of flaviviruses. Previous studies demonstrated that NS1' plays a vital role in virulence, but the mechanism is unclear. In this study, an NS1' defected(rG66A) virus was generated. We found that rG66A virus was less virulent than its parent virus(pSA14) in wild-type mice. However, similar mortality caused by the two viruses was observed in an IFNAR knockout mouse model. Moreover, we found that rG66A virus induced a greater type Ⅰ interferon(IFN) response than that by pSA14, and JEV NS1' significantly inhibited the production of IFN-b and IFN-stimulated genes. Taken together, our results reveal that NS1' plays a vital role in blocking type I IFN production to help JEV evade antiviral immunity and benefit viral replication.

Screening of novel synthetic derivatives of dehydroepiandrosterone for antivirals against flaviviruses infections

Flaviviruses are important arthropod-borne pathogens that represent an immense global health problem.Their unprecedented epidemic rate and unpredictable clinical features underscore an urgent need for antiviral interventions.Dehydroepiandrosterone(DHEA)is a natural occurring adrenal-derived steroid in the human body that has been associated in protection against various infections.In the present study,the plaque assay based primary screening was conducted on 32 synthetic derivatives of DHEA against Japanese encephalitis virus(JEV)to identify potent anti-flaviviral compounds.Based on primary screening,HAAS-AV3026 and HAAS-AV3027 were selected as hits from DHEA derivatives that exhibited strong antiviral activity against JEV(IC_(50)=2.13 and 1.98μmol/L,respectively)and Zika virus(ZIKV)(IC_(50)=3.73 and 3.42μmol/L,respectively).Mechanism study indicates that HAAS-AV3026 and HAAS-AV3027 do not exhibit inhibitory effect on flavivirus binding and entry process,while significantly inhibit flavivirus infection at the replication stage.Moreover,indirect immunofluorescence assay,Western blot analyses,and quantitative reverse transcription-PCR(qRT-PCR)revealed a potent antiviral activity of DHEA derivatives hits against JEV and ZIKV in terms of inhibition of viral infection,protein production,and viral RNA synthesis in Vero cells.Taken together,our results may provide a basis for the development of new antivirals against flaviviruses.