The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB), or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like Receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB, and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

Unexpected intraoperative need for vascular surgical expertise occurs often enough that vascular surgeons should be regarded as an essential operating room resource to the general operating room, nonvascular surgeons, and their patients. Intraoperative vascular surgical consultation in support of other surgeons requires a high level of open technical operative skills and is time and labor intensive.

BackgroundSpontaneous skull base defects can result in life‐threatening intracranial complications (ICCs), including meningitis and pneumocephalus. Endoscopic skull base reconstruction (ESBR) has traditionally been the treatment of choice, but its impact upon ICCs is not known. In this study, we aimed to describe the incidence rate of preoperative ICCs in patients with spontaneous skull base defects, risk factors associated with ICC development, and the impact of surgical repair on the incidence rate of ICCs.MethodsA retrospective review was performed of all spontaneous skull base defects undergoing ESBR from 2005 to 2019 at 2 academic tertiary care medical centers. The incidence rate of ICCs and the demographics information and risk factors were collected.ResultsIn 222 spontaneous skull base defects, preoperative ICCs occurred in 46 subjects (20.7%) with an incidence rate of 22.7 per 100 person‐years. Factors significantly associated with preoperative ICCs included symptom duration, reduced body mass index (BMI), resolved cerebrospinal fluid rhinorrhea, and location in the frontal or lateral sphenoid sinuses. Endoscopic repair was successful in 97.2% of subjects and the postoperative ICC incidence rate was significantly reduced at 0.8 per 100 person‐years (p < 0.001).ConclusionSpontaneous skull base defects pose significant risk for life‐threatening ICCs. Our findings reveal significantly elevated odds of ICC development associated with resolved CSF rhinorrhea, lower BMI, longer duration of symptoms, and defect location. Endoscopic repair is highly successful with low morbidity and significantly reduces the incidence rate of intracranial complications.

TLRs are critical for host defense and innate immunity. Emerging evidence also supports a role for TLRs in many chronic inflammatory diseases, including inflammatory eye disease, known as uveitis. The activation of TLR4 by endotoxin induces a standard model of murine uveitis. How activation of additional TLRs influences the onset and/or severity of anterior uveitis has not been examined. We sought to elucidate the potential of TLRs (TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7/8, and TLR9) to trigger uveitis in mice. Directly stimulated iris/ciliary body explants demonstrated a marked increase in production of inflammatory cytokines TNF-α, IL-6, IP-10/CXCL10, MCP-1, and KC with relatively little production of IFN-γ, IL-10, IL-12p40, IL-12p70, IL-17, IL-1β, IL-4, or RANTES. The cytokine-response profiles were comparable amongst the TLR agonists, albeit some differences were noted, such as greater IP-10 production following TLR3 activation. Intra-ocular injection of TLR agonists increased leukocyte interactions with the endothelium of the iris vasculature and resulted in chemotaxis into the iris tissue. Assessment of leukocytic responses by ivt videomicroscopy and histology revealed quantitative differences amongst responses to the TLR agonists with respect to the timing and numbers of rolling, adhering, iris-infiltrating, and aqueous humor-infiltrating cells, along with cytokine levels in vivo. Our data demonstrate the eye's responsiveness to a diverse array of microbial products, which activates TLRs, and reveal differences in relative cellular response among the various TLR agonists in vivo.

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