Steven K. Juhn

Prostaglandins in squamous cell carcinoma of the head and neck: A preliminary study

It has already been demonstrated in human and animal systems that PGE2 is a suppressor signal For many immune functions. These include T‐lymphocyte blastogenesis, natural killer cell activity, and cytolytic T‐lymphocyte activity. These functions are important for destruction of tumor cells. Conceivably, suppression of these functions by excessive PGE2 restricts tumor cell kill, and reversal of suppression by an inhibitor of prostaglandin synthesis such as indomethacin could increase tumor cell kill. The purpose of this study was to determine the kind of prostaglandins (PGs) produced by tissues with squamous cell carcinoma of head and neck and to measure the concentrations of PGE2, 6‐keto‐PGF1a, and thromboxane (Tx) B2 in the tumor tissue and in the corresponding control tissue.

Cellular Events Involved in Middle Ear Fluid Production

Inflammation of the middle ear and mastoid can result in fluid which is serous, mucoid, bloody, purulent or a combination of the above. Middle ear fluid problems are more common in children. That some of these problems in children can become refractory and lead to complications, including chronic granulomatous otitis media and mastoiditis, seems to be a valid clinical observation. This suggests that predisposing underlying factors for middle ear fluid problems and certain forms of chronic inflammatory mastoid disease exist as common denominators for both entities.

Pathogenesis of Otitis Media

Pathogenesis of otitis media was studied in humans and various animal models primarily from a pathological and chemical point of view. Findings were correlated and interpreted for various forms of otitis media in longitudinal and parallel studies, including acute purulent otitis media (POM), serous otitis media (SOM), mucoid or secretory otitis media (MOM), and chronic suppurative otitis media (COM), especially as regards the continuum or interrelated changes of various groups. Purulent otitis media was produced in chinchillas by direct inoculation of less than 100 pneumococci into the middle ear space. Serous otitis media was produced in chinchillas and cats following Eustachian tube obstruction with silicone. Mucoid otitis media followed the development of SOM in cats after two to four weeks of tubal occlusion. Samples of middle ear effusion (MEE) and serum, obtained from children with SOM and MOM after myringotomy for ventilation tube placement, were evaluated. The three components studied were MEE, epithelium and the subepithelial space (SES). Inflammatory changes in the SES were significant for all forms of otitis media, but especially for POM and SOM. Epithelial metaplasia to secretory cells was most prominent in MOM. Chemical factors involved in pathogenesis and defense were studied. Lactic dehydrogenase and lysozyme, chemical indicators of inflammatory activity, were greater in POM and MOM than in SOM. Immunoglobulins (A, G, & M) were greater in MOM than in SOM. The similarity of findings between the groups suggests a strong relationship between them. The ability of certain types of otitis media to evolve into another substantiates the concept of the continuum for some patients. Pathogenesis is dependent upon various extrinsic factors of etiopathogenesis, while the form that otitis media takes seems to rely mostly on relative activity of the SES and the epithelium.

Review of Round Window Membrane Permeability

The round window membrane (RWM) is permeable to certain biological substances. Those substances that can pass through the RWM have the potential to cause inner ear damage, leading to functional disturbances. The RWM is permeable to water, and the existence of osmotically active substances in the middle ear cavity can induce an alteration of inner ear fluid osmolality, leading to membrane displacement. However, several limiting factors exist that prevent free passage of substances from the middle ear to the inner ear. These include the morphological barrier of the three-layered RWM, the molecular weight of the substances, and the nature and concentration of substances in the middle ear cavity. The degree and duration of the inflammation in the middle ear cavity, as well as the morphological integrity of the RWM, also play an important role in controlling the passage of noxious substances into the inner ear. Further characterization of the factors involved in RWM permeability, and clarification of the mechanisms of the inner ear damages caused by substances passing into the inner ear through the RWM, are necessary for an understanding of the inner ear dysfunction caused by middle ear inflammation.

Nature of Blood-Labyrinth Barrier in Experimental Conditions

The blood-labyrinth barrier is a concept that has evolved based on marked difference in chemical composition between perilymph and blood. Studies reported here have been designed to manipulate physiologic, metabolic, and pharmacologic conditions in experimental animals in order to determine the characteristics of this regulatory mechanism. Tracer studies of uptake of sodium, calcium, and albumin from blood into perilymph showed that these substances penetrate into inner ear fluids quite slowly. Injections of ototoxic substances (kanamycin, furosemide) show limited transport of these agents into perilymph. Another ototoxic agent, ethacrynic acid, was found to transiently reduce the transport of sodium into perilymph. Administration of an osmotic agent (urea) resulted in a parallel but delayed elevation of perilymph concentration. The possible role of alteration of blood-labyrinth barrier in inner ear disorders has been discussed.

The role of inflammatory mediators in the pathogenesis of otitis media and sequelae.

This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K+ recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued.

Mucociliary activity and histopathology of sinus mucosa in experimental maxillary sinusitis : a comparison of systemic administration of antibiotic and antibiotic delivery by polylactic acid polymer

To evaluate the efficacy of antibiotic delivered by polyactic acid (PLA) polymer in sinusitis, we induced maxillary sinusitis in 32 New Zealand white rabbits by occluding the sinus ostium and inoculating the sinus cavity with Streptococcus pneumoniae. The rabbits were divided into three groups consisting of group 1 (control group, 8 rabbits), which was treated only by reopening the ostium; group 2, which was treated by both reopening the ostium and injecting ampicillin intramuscularly (40 mg/kg/day in three divided doses, 12 rabbits); and group 3 (12 rabbits) in which a piece of PLA‐polymer ampicillin (0.326 mg) sheet (1.5 × 1.5 cm) was placed within the sinus after re‐establishing ostial patency.

Barrier Systems in the Inner Ear

Because of the highly complicated function of the central nervous system and sensory organs, barrier systems have necessarily developed to ensure stability of the extracellular fluids bathing these organs. Several barrier systems which can influence the composition of the inner ear fluids are discussed. They are the 1) blood-labyrinth barrier, 2) cerebrospinal fluid-labyrinth barrier, and 3) middle ear-labyrinth barrier. The experimental data are shown to indicate that these barriers serve to protect the inner ear through selective permeability. Arachidonic acid metabolites, particularly compounds of the prostaglandin series, were identified in perilymph, and were increased by the administration of stress-related hormones, and decreased after aspirin injection. The inner ear fluid composition responds to the changes of the surrounding fluid containing compartments. However, the degree of response appears to depend on the level of changes induced in the surrounding compartments. The concept of a threshold concentration of toxic substances in middle ear effusion to induce inner ear damage is also proposed.

A combination antioxidant therapy prevents age-related hearing loss in C57BL/6 mice

OBJECTIVE: Age-related hearing loss (ARHL) is characterized by gradual, progressive sensorineural hearing loss, which impairs communication, lending to clinical depression and social withdrawal. There are currently no effective treatments for ARHL. The purpose of this study is to evaluate the potential of a combination antioxidant therapy in preventing ARHL. STUDY DESIGN: Randomized controlled trial. SETTING: Animal study. SUBJECTS AND METHODS: C57BL/6 mice, a recognized animal model of ARHL, were assigned to one of three groups: early treatment (n = 12), late treatment (n = 9), or control group (n = 9). Treatment groups of mice were fed with a combination agent comprising six antioxidant agents that target four sites within the oxidative pathway: L-cysteine-glutathione mixed disulfide, ribose- cysteine, NW-nitro-L-arginine methyl ester, vitamin B12, folate, and ascorbic acid. Auditory brainstem response (ABR) thresholds were recorded at baseline and every three months following initiation of treatment. RESULTS: Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies (P < 0.001). The ABR threshold shift at 12 months of age for the control group was 34.7 dB with a 95% confidence interval (CI) of ± 1.6. The mean threshold shifts for the early and late treatment groups were 7.5 dB (±0.87, 95% CI) and 9.2 dB (±1.6, 95% CI). CONCLUSION: Combination antioxidant therapy effectively decreased threshold shifts on ABR within an animal model of ARHL. Combination antioxidant therapy, with further research and investigation, may provide a safe and cost-effective method of preventing presbycusis in the growing elderly population.

Ototoxicity of propylene glycol in experimental animals

The ototoxicity of antibiotics given either systemically or topically has been recently recognized. However, the ototoxicity of topically applied alcohols and other solvents used as vehicles for drugs has not been well recognized. One of the most common solvents, propylene glycol, was chosen for this study, and this agent in various concentrations was instilled into the middle ear of guinea pigs and chinchillas for various periods of time. Its effect on the function of the cochlea was studied as well as the histopathologic changes in the temporal bones. Deterioration of the cochlear microphonics and the endocochlear direct current potential was found. A 10 per cent solution applied for six days caused a reduction in the cochlear microphonics. Fifty per cent or stronger solution always caused a reduction in the cochlear microphonics. The deterioration in the cochlear microphonics persisted one month. Dose related changes in the endocochlear potential were noted. Morphologic changes were severe and included granulation tissue in the middle ear and destruction and ossification of the auditory bulla and bony cochlea. Propylene glycol should not be used in the ear that has a perforation of the tympanic membrane.