Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells ...play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is estimated that hearing loss currently affects more than 1.5 billion people, or approximately 20% of the global population; however, presently, there are no Food and Drug Administration-approved ...therapeutics or prophylactics for this condition. While continued research on the development of otoprotective drugs to target this clear unmet need is an obvious path, there are numerous challenges to translating promising therapeutic candidates into human clinical testing. The screening of promising drug candidates relies exclusively on preclinical models. Current models do not permit the rapid high-throughput screening of promising drug candidates, and their relevance to clinical scenarios is often ambiguous. With the current study, we seek to understand the drug permeability properties of the cadaveric tympanic and round window membranes with the goal of generating knowledge that could inform the design and/or evaluation of in vitro organotypic models. The development of such models could enable the early high-throughput screening of topical therapeutic candidates and should address some of the limitations of currently used animal models.
To determine whether a community engagement approach can provide feedback for implementation of valuable measures to improve the outcome of a clinical trial.
Review of the results from a Community ...Engagement Studio (CE Studio) for the ValEAR trial: an NIH-funded, multi-institutional study designed to research the efficacy of valganciclovir in the treatment of congenital cytomegalovirus (cCMV)-induced hearing loss. Participants were given information about the trial then asked a series of questions to assess their input on the merits or weaknesses affecting their participation in the trial.
Thirteen parents whose children have congenital CMV infection were recruited for the CE Studio. The overall theme from the responses was a desire to advance the field but a need to clearly understand the risks and benefits of participation. Many requested more educational resources, more printed materials, or greater access to researchers if questions arose. Many welcomed having patient stories and information displayed in a dedicated website or through social media.
This community engagement approach provided useful feedback from families similar to those expected to be potential enrollees in the CMV ValEAR trial. In response to parental comments, two educational videos were created: one on the general topic of cCMV and the other specific to the CMV ValEAR trial. Researchers who wish to optimize their clinical trial's success should consider incorporating a CE Studio into their study design.
The pose (i.e., position and orientation) of a guinea-pig cochlea can be accurately estimated using externally observable features, without requiring computed-tomography (CT) scans.
Guinea pigs are ...frequently used in otologic research as animal models of cochlear-implant surgery. In robot-assisted surgical insertion of cochlear-implant electrode arrays, knowing the cochlea pose is required. A preoperative CT scan of the guinea-pig anatomy can be labeled and registered to the surgical system, however, this process can be expensive and time consuming.
Anatomical features from both sides of 11 guinea-pig CT scans were labeled and registered, forming sets. Using a groupwise point-set registration algorithm, errors in cochlea position and modiolar-axis orientation were estimated for 11 iterations of registration where each feature set was used as a hold-out set containing a reduced number of features that could all be touched by a motion-tracking probe intraoperatively. The method was validated on 2000 simulated guinea-pig cochleae and six physical guinea-pig-skull cochleae.
Validation on simulated cochleae resulted in cochlea-position estimates with a maximum error of 0.43 mm and modiolar-axis orientation estimates with a maximum error of 8.1 degrees for 96.7% of cochleae. Physical validation resulted in cochlea-position estimates with a maximum error of 0.80 mm and modiolar-axis orientation estimates with a maximum error of 12.4 degrees.
This work enables researchers conducting robot-assisted surgical insertions of cochlear-implant electrode arrays using a guinea-pig animal model to estimate the pose of a guinea-pig cochlea by locating six externally observable features on the guinea pig, without the need for CT scans.
Objective
Compare hearing outcomes utilizing standard, prolonged and delayed ganciclovir (GCV) therapy in a murine model of cytomegalovirus (CMV).
Methods
BALB/c mice were inoculated with mouse ...cytomegalovirus (mCMV) or saline via intracerebral injection on postnatal day 3 (p3). Intraperitoneal GCV or saline was administered at 12 h intervals for the duration of the standard (p3‐p17), delayed (p30‐p44), or prolonged treatment windows (p3‐p31). Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing at 4, 6, and 8 weeks of age. Blood and tissue samples were harvested from mice on p17 and p37 one hour after GCV administration, and their concentrations were assessed via liquid chromatography‐mass spectrometry.
Results
A delayed course of GCV improved ABR but not DPOAE thresholds in mCMV‐infected mice. A prolonged course of GCV did not provide better hearing thresholds than those administered standard treatment. The average GCV concentration in all 17‐day‐old mice tissue was significantly higher than those in older 37‐day‐old mice.
Conclusion
Delayed GCV treatment provided a hearing benefit on ABR over untreated mCMV infected mice. Prolonged CGV administration showed no benefit compared to a shorter duration GCV treatment. GCV drug concentrations both systemically and in the cochlea are much lower in older mice. These results have potential implications for the clinical management of cCMV infected children.
Level of Evidence
NA Laryngoscope, 134:433–438, 2024
In this paper we show that delayed ganciclovir (GCV) treatment provided improved auditory brainstem response (ABR) thresholds in mCMV infected mice. A prolonged course of GCV did not provide better hearing thresholds than those administered standard treatment. The average GCV concentration in younger 17‐day old mice was significantly higher than those in older 37‐day old mice. The results have important potential implications for the clinical management of cCMV infected children.
With an emphasis on patient-centered care and provider transparency, patient satisfaction measures have become a key indicator of healthcare quality. Using the Press Ganey Outpatient Medical Practice ...Survey (PGOMPS), we sought to determine key factors that impact patient satisfaction.
We conducted a retrospective review of new pediatric (<18 years old) outpatient otolaryngology visits between January 1, 2014 and December 31, 2018 at a children's hospital clinic and satellite clinics. Univariate and multivariate binary logistic regression analysis were used to determine factors correlated with patient satisfaction for both the PGOMPS Total Score and Provider Sub-Score.
A total of 1,050 patient or parent responses were included. The mean patient age was 5.6 ± 5.0 years with 54.7% identified as male. Univariate analysis demonstrated that for each 10-min increase in Total Wait Time, the odds of being satisfied were significantly decreased on both the Total Score (odds ratio OR 0.5; P < 0.001) and Provider Sub-Score (OR 0.8; P < 0.001). Furthermore, for each additional 5-year increase in patient age, patients were significantly more likely to report satisfaction on Total Score (OR 1.21; P = 0.011). Multivariate analysis revealed that the odds of achieving satisfaction for each decile increase in Total Wait Time were 0.5 for Total Score (P < 0.001) and 0.8 for Provider Sub-Score (P < 0.001), independent of patient age, sex, insurance category, socioeconomic disadvantage level, and patient community type.
Wait time is a significant factor impacting patients’ likelihood of being satisfied with their overall care in a pediatric otolaryngology clinic setting.
Zika virus (ZIKV) can cause various diseases in offspring after congenital infection. The purpose of this study was to identify disease phenotypes in pups exposed to ZIKV in utero. Female ...interferon-α/β, -γ receptor knockout mice (AG129) were infected intraperitoneally with ZIKV 7.5 days' post coitus (dpc). Viral RNA, antigen and infectious virus were detected in some, but not all, maternal and fetal tissues at various times during gestation. Fetuses of infected dams had significant intrauterine growth restriction (IUGR), which was more pronounced as females neared parturition. Pups born to infected dams were significantly smaller and had significantly shortened skull lengths, as determined by measurement with a caliper and by micro-CT analysis, as compared with age-matched controls. Growth rates of exposed pups after birth, however, was similar to sham-exposed offspring. Viral RNA was detected in pups of infected dams after birth. A lower survival rate was observed in neonates exposed to ZIKV in utero. A mortality rate of over 50%, attributed to consequences of ZIKV infection, occurred after birth in pups born to infected dams. A transient hearing loss was observed in some animals exposed to virus in utero. No motor deficits or cognitive deficits were detected using running wheel or viral paresis scoring assays. Abnormalities in offspring included smaller size, shorter skull length and increased neonatal mortality, while the only functional deficit we could detect was a low incidence of transient hearing loss.
Proteasomes drive the selective degradation of protein substrates with covalently linked ubiquitin chains in eukaryotes. Although proteasomes are distributed throughout the cell, specific biological ...functions of the proteasome in distinct subcellular locales remain largely unknown. We report that proteasomes localized at the centrosome regulate the degradation of local ubiquitin conjugates in mammalian neurons. We find that the proteasomal subunit S5a/Rpn10, a ubiquitin receptor that selects substrates for degradation, is essential for proteasomal activity at centrosomes in neurons and thereby promotes the elaboration of dendrite arbors in the rodent brain in vivo. We also find that the helix-loop-helix protein Id1 disrupts the interaction of S5a/Rpn10 with the proteasomal lid and thereby inhibits centrosomal proteasome activity and dendrite elaboration in neurons. Together, our findings define a function for a specific pool of proteasomes at the neuronal centrosome and identify a biological function for S5a/Rpn10 in the mammalian brain.
Display omitted
•The ubiquitin receptor S5a/Rpn10 promotes dendrite growth in primary neurons and in vivo•S5a/Rpn10 acts at the centrosome to regulate proteasome activity and dendrite development•The HLH protein Id1 suppresses S5a/Rpn10-dependent dendrite morphogenesis•Id1 disrupts S5a/Rpn10-mediated degradation of ubiquitin conjugates at the centrosome
Although proteasomes are distributed throughout the cell, specific functions of proteasomes in distinct subcellular locales remain unknown. Here, Kim, Bonni, and colleagues report that proteasomes localized at the centrosome regulate the degradation of local ubiquitin conjugates in mammalian neurons. The ubiquitin receptor S5a/Rpn10 is essential for proteasomal activity at centrosomes and promotes dendrite growth and elaboration. They also show that the helix-loop-helix protein Id1 disrupts the interaction of S5a/Rpn10 with the proteasomal lid, thereby inhibiting centrosomal proteasome activity and dendrite elaboration.
Objectives/Hypothesis
To describe the clinical presentation, management, and complications associated with button battery impaction in the aerodigestive tract in children.
Study Design
Retrospective ...case series.
Methods
This multi‐institutional study, endorsed by the American Society of Pediatric Otolaryngology research consortium, is a retrospective medical record review, including all children at five tertiary‐care institutions presenting with button batteries impacted in the aerodigestive tract between January 2002 and December 2014. Battery type/size, duration and location of impaction, presenting symptoms, treatment, complications, and outcomes were examined.
Results
Eighty‐one patients were included (64.2% male), with ingestion witnessed in 20 (24.7%). Median age at presentation was 3 years (range, 1 week–14 years). Median time from diagnosis to removal was 2.5 hours (range, 0.4–72 hours). Locations included the esophagus (n = 48), hypopharynx (n = 1), stomach (n = 6), nasal cavity (n = 22), and ear canal (n = 4). Most common symptoms for esophageal/hypopharyngeal impactions included dysphagia (26.5%), nausea/vomiting (26.5%), drooling (24.5%), cough (18.4%), and fever (18.4%). Most common symptoms for nasal impactions included epistaxis (54.6%), rhinorrhea (40.9%), nasal pain (27.3%), and fever (22.7%). Almost all esophageal impactions were from 3‐V (89.5%), 20‐mm (81.8%) lithium batteries. Severe esophageal complications included stricture (28.6%), perforation (24.5%), tracheoesophageal fistula formation (8.2%), pneumothorax (4.1%), and bilateral true vocal fold paresis (4.1%). Nasal complications included necrosis (59.1%), septal perforation (27.3%), and saddle nose deformity (4.5%). Duration of impaction correlated with an increased likelihood of persistent symptoms only for nasal batteries (P = .049).
Conclusions
Button batteries in the upper pediatric aerodigestive tract or ear canal should be considered a surgical emergency, requiring urgent removal and careful vigilance for complications.
Level of Evidence
4 Laryngoscope, 131:E298–E306, 2021
PDF
