Patricia A. Schachern

Experimental studies on round window structure: Function and permeability†

Current research and an overall review of 12 years of round window membrane studies is presented. The approach, rationale, and concepts that have evolved from the studies are described. An ultrastructural study of the round window membrane of rhesus monkeys disclosed three basic layers: an outer epithelium, a middle core of connective tissue, and an inner epithelium. Morphologic evidence in monkeys, cats, and chinchillas suggests that these layers of the round window participate in absorption and secretion of substances to and from the inner ear, and that the entire membrane could play a role in the defense system of the ear. Cationic ferritin, horseradish peroxidase, 1‐μm latex spheres, and neomycin‐gold spheres placed in the middle ear of these experimental animals were observed to traverse the round window membrane through pinocytotic vesicles. Three‐micron latex spheres and anionic ferritin were not incorporated by the membrane. Cationic ferritin and 1‐μm latex spheres placed in perilymph were incorporated by the inner epithelial cells, suggesting absorptive capabilities of the round window membrane. Cationic ferritin was observed within the mesothelial cells underlying the scala tympani side of the basilar membrane, suggesting a role for these cells in the inner‐ear defense system. A review of the subject and a general perspective from the authors viewpoint are discussed.

Prolonged expression of a lysosomal enzyme in mouse liver after Sleeping Beauty transposon-mediated gene delivery: implications for non-viral gene therapy of mucopolysaccharidoses

The Sleeping Beauty (SB) transposon system is a non‐viral vector system that can integrate precise sequences into chromosomes. We evaluated the SB transposon system as a tool for gene therapy of mucopolysaccharidosis (MPS) types I and VII.

Histopathology of sudden hearing loss

Eleven temporal bones from eight patients who had clinical histories of sudden hearing loss (SHL) were studied to assess the possible etiopathogenesis. The origin of SHL in seven ears from five patients was obscure, but appeared to be due to multiple causes. Common histopathologic changes in the cochlea, although complex, included atrophy of the organ of Corti and loss of cochlear neurons. Loss of cochlear neurons was the main finding in ears of viral infection. Labyrinthine fibrosis and formation of new bone were seen in two ears associated with vascular insult and in two ears of autoimmune disease. Different histopathologic findings causing SHL were observed even in cases with the same etiology. A case of SHL showing endolymphatic hydrops as the main histopathologic finding is described.

Systemic Correction of Storage Disease in MPS I NOD/SCID Mice Using the Sleeping Beauty Transposon System

The Sleeping Beauty (SB) transposon system is a nonviral vector that directs transgene integration into vertebrate genomes. We hydrodynamically delivered SB transposon plasmids encoding human alpha-L-iduronidase (hIDUA) at two DNA doses, with and without an SB transposase gene, to NOD.129(B6)-Prkdc(scid) IDUA(tm1Clk)/J mice. In transposon-treated, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with mucopolysaccharidosis type I (MPS I), plasma IDUA persisted for 18 weeks at levels up to several hundred-fold wild-type (WT) activity, depending on DNA dose and gender. IDUA activity was present in all examined somatic organs, as well as in the brain, and correlated with both glycosaminoglycan (GAG) reduction in these organs and level of expression in the liver, the target of transposon delivery. IDUA activity was higher in the treated males than in females. In females, omission of transposase source resulted in significantly lower IDUA levels and incomplete GAG reduction in some organs, confirming the positive effect of transposition on long-term IDUA expression and correction of the disease. The SB transposon system proved efficacious in correcting several clinical manifestations of MPS I in mice, including thickening of the zygomatic arch, hepatomegaly, and accumulation of foamy macrophages in bone marrow and synovium, implying potential effectiveness of this approach in treatment of human MPS I.

Temporal bone histopathology in chronically infected ears with intact and perforated tympanic membranes

Chronic suppurative otitis media has been clinically defined as a chronic discharge from the middle ear in the presence of a perforation of the tympanic membrane. However, irreversible tissue pathology in the middle ear or mastoid can occur behind an intact tympanic membrane. One hundred forty‐four human temporal bones with chronic otitis media were divided into two groups: those with perforated (28) and those with nonperforated (116) tympanic membranes. The histopathological findings of their middle ears were compared.

Systemic vasculitis: a temporal bone histopathologic study.

Systemic vasculitis includes a broad spectrum of disorders that may involve blood vessels of any size in any organ system. Systemic vasculitis is associated with immunopathogenic mechanisms. Sixteen temporal bones from eight persons were studied to determine histopathologic changes that occur in systemic vasculitis. Three persons had Wegeners granulomatosis, two had polyarteritis nodosa, and three had systemic lupus erythematosus. Otitis media was seen in 15 ears, with ten ears showing chronic middle ear changes and two showing fibrotic inner ear changes. In Wegeners granulomatosis, granulation tissue was observed around the eustachian tube and protympanum, and in polyarteritis nodosa, inflammatory cell infiltrate and thickened blood vessels were observed around the facial nerve. Although sensorineural hearing loss has been described clinically in systemic lupus erythematosus, the present report describes findings in temporal bones, including severe fibrosis and new bone formation throughout the inner ear.

Histopathology of human temporal bone after cis-platinum, radiation, or both ☆ ☆☆ ★

Preserving organs by use of multiple modalities has become protocol in treating squamous cell carcinomas of the head and neck, but cis-platinum and radiation can impair hearing. To determine the effect of cis-platinum, radiation, or a combination of these treatments on the temporal bone, we studied histopathologic slides of 15 human temporal bones: four after cis-platinum, five after radiation, two after combined treatment, and four from normal controls. Hair cells and cells in spiral ganglia were counted in reconstructed organs of Corti. Lumen-to-diameter indexes in arterioles near facial nerves were quantified for four normal controls and seven irradiated patients. Available audiograms were compared. Decreased spiral ganglion cells, loss of inner and outer hair cells, and atrophy of stria vascularis were demonstrated in groups receiving cis-platinum, radiation, and combinations, compared with age-matched controls. Arterioles around facial nerves demonstrated fibrinous clots within the intima, endothelial proliferation, and hypertrophy and fibrosis of vascular walls in smooth muscle. Fibrosis in connective tissue was clearly progressive after radiation. Cis-platinum and radiation can contribute to otologic sequelae, including sensorineural hearing losses, vascular changes, serous effusion, or fibrosis. Prophylactic treatments and techniques to deliver them should be considered for protection of temporal bones and preservation of hearing after oncologic modalities. (Otolaryngol Head Neck Surg 1998;118:825–32.)

Pathogenesis of Tympanosclerosis

In spite of the wealth of information on the clinical, histologic, and pathologic aspects of tympanosclerosis, the pathogenesis of tympanosclerosis is still unclear. In an attempt to understand the pathogenesis, 319 human temporal bones from 196 individuals with otitis media were studied. The extent and nature of tympanosclerosis and the characteristics of the otitis media associated with it were studied. Forty-five temporal bones from 35 individuals with otitis media were found to have tympanosclerosis, giving an incidence of 14.1%. It was seen most commonly in individuals over 40 years of age (86.7%). The male-to-female ratio was 1.6:1. The most common site of occurrence was the tympanic membrane (88.9%). Tympanosclerosis was seen more often in the anterior and posterior inferior quadrants of the tympanic membrane and that, too, in a central position. Tympanosclerosis was seen more commonly in temporal bones with irreversible inflammatory changes, and in this group, late plaques were more commonly seen than early or intermediate plaques. Audiometric charts failed to show any direct relationship between extent of tympanosclerosis and the severity of hearing loss. The only audiometric finding of any consequence was a mixed hearing loss in the presence of middle ear tympanosclerosis. (OTOLARYNGOL HEAD NECK SURG 1993;109:413–20.)

Otologic Histopathology of Fabry's Disease

Fabrys disease is a rare progressive X-linked recessive disorder of glycosphingolipid metabolism. The accumulation of glycosphingolipids occurs in virtually all areas of the body, including the endothelial, perithelial, and smooth-muscle cells of blood vessels, the ganglion cells of the autonomic nervous system, and the glomeruli and tubules of the kidney. Although otologic symptoms have been described in these patients, to our knowledge there have been no temporal bone histopathologic reports. We describe the clinical histories, audiometric results, and temporal bone findings of two patients with this rare disorder. Both patients demonstrated a bilateral sloping sensorineural hearing loss audiometrically. Middle ear findings of seropurulent effusions and hyperplastic mucosa were seen in all four temporal bones. Strial and spiral ligament atrophy in all turns, and hair cell loss mainly in the basal turns, were also common findings. The number of spiral ganglion cells was reduced in all temporal bones; however, evidence of glycosphingolipid accumulation was not observed in the spiral ganglia.

Cochlear changes in patients with type 1 diabetes mellitus.

OBJECTIVE: To evaluate the effects of diabetes on cochlear elements in human beings. STUDY DESIGN AND SETTING: Twenty-six temporal bones (mean age, 37.5 years) with type 1 diabetes and 30 age-matched controls were examined by light microscopy. We compared the findings of cochlear vessels, hair cells, spiral ganglion cells, and cochlear lateral walls. RESULTS: In diabetics, the walls of vessels of the basilar membrane (P < 0.001) and vessels of the stria vascularis were (P < 0.01) significantly thicker in all turns and loss of outer hair cells (OHCs) was significantly greater in the lower basal turn (P < 0.01). Atrophy of the stria vascularis in all turns (P < 0.0001) and loss of spiral ligament cells in upper turns (P < 0.01) were significantly higher than controls. No significant difference was obtained in the number of spiral ganglion cells between groups. CONCLUSION: This study suggests that type 1 diabetes mellitus can cause cochlear microangiopathy and subsequently degeneration of cochlear lateral walls and OHCs.