Faculty Bibliography

Cochlear implantation continues to evolve as an accepted method of rehabilitating profoundly hearing impaired adults and children. The current trend is toward installing implants in children at a younger age, when they demonstrate greater central nervous system plasticity and are more likely to enjoy a favorable outcome. Implantation is now routinely performed on children at 18 months of age, or earlier if there is evidence of postmeningitic ossification. New speech processing strategies are contributing to better results, in adults and children. The complication rate from implantation surgery continues to be at an acceptably low level

The petrous apex is the most inaccessible portion of the temporal bone and surgical exposure presents considerable challenge. The transmastoid precochlear approach offers a direct intra temporal route to this region, providing good visual exposure with cochlea preservation. An anatomic study of 20 human temporal bones was performed to delineate the landmarks for this approach. Measurements to the tegmen tympani, carotid artery, and the anterior-superior limit of the cochlea were made from the cochleariform process, a constant landmark in the middle ear. Distances to the tegmen averaged 5.4 mm (range: 3.5-9 mm), to the carotid artery 9.3 mm (8-11 mm), and the cochlea 3.1 mm (2-5 mm). The entry to the apex admitted an average burr size of 3.5 mm (2-7 mm). We anticipate this approach will prove useful in the treatment of benign petrous apex lesions.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

The possibility that serum ferritin is a secreted protein and an acute phase reactant regulated by inflammatory hormones and iron was examined in a hepatic cell line that secretes plasma proteins. Differentiated rat hepatoma cells released albumin and ferritin into the medium, as determined by rocket immunoelectrophoresis and isolation of ferritin by standard procedures plus immunoaffinity chromatography, following labeling with radioactive amino acid. Administration of interleukin-1-beta (IL-1) or tumor necrosis factor-alpha (TNF) doubled the amounts of ferritin released into the medium over 24 and 48 hours. Together, the cytokines had more than an additive effect. Albumin secretion was diminished by IL-1, but not TNF. Iron, administered as an iron dextran complex or as a 1:1 chelate with nitrilotriacetate (Fe-NTA), also enhanced ferritin release, but had no effect on albumin. Intracellular ferritin concentrations did not change significantly with cytokine treatment, but increased in response to iron. With or without treatments, release of ferritin and albumin from cells into the medium was inhibited by brefeldin A, an inhibitor of Golgi function. The effect of each of the cytokines and of iron on ferritin and albumin was also blocked by dichlorofuranosylbenzimidazole (DRB), an inhibitor of transcription. The stimulatory effect of Fe-NTA on ferritin secretion was diminished by TNF, and this was partially counteracted by IL-1, indicating additional regulatory complexity. These results show for the first time that hepatic cells secrete ferritin, that this ferritin secretion is regulated by iron and inflammatory cytokines, and that the mechanisms of regulation differ from those for intracellular ferritin. The results would explain why serum ferritin increases in inflammation or when iron flux is enhanced.

BACKGROUND AND OBJECTIVES: Esophagogastric anastomotic leaks are a major source of morbidity after esophagectomy. Occult ischemia of the mobilized gastric fundus is an important etiological factor for this failure of healing. To test the hypothesis that ischemic conditioning (delay phenomenon) could improve esophagogastric anastomotic healing, anastomotic healing was studied in a rodent model of partial gastric devascularization. METHODS: Thirty-four Sprague-Dawley rats (two groups of 17 rats) underwent partial gastric devascularization and creation of esophagogastric anastomoses. In the acute ischemia group, devascularization and anastomosis were done at the same laparotomy. In the ischemic conditioned group, devascularization was done 3 weeks before anastomosis. Gastric tissue perfusion was assessed by laser-Doppler flowmetry before and after devascularization in both groups, and 3 weeks after devascularization in the ischemic conditioned group. All rats were killed 4 days after anastomosis, and the wounds assessed for dehiscence, breaking strength, and hydroxyproline concentration. RESULTS: Gastric tissue perfusion, measured in tissue perfusion units (TPU) decreased immediately after devascularization (before: 73.6 +/- 12.1 TPU; after: 25.0 +/- 6.5 TPU; P < 0.001). After 3 weeks, gastric tissue perfusion returned to baseline values in the ischemic conditioned rats (before: 72.3 +/- 11.0 TPU; 3 weeks, 71.1 +/- 15.1 TPU; P < 0.80). Ischemic conditioned rats had fewer anastomotic leaks (2 vs. 9, P < 0.023) and higher anastomotic wound breaking strengths (2.35 +/- 1.05 N vs. 1.56 +/- .76 N, P < 0.02) than the acute ischemic rats. Anastomotic would hydroxy-proline concentration was not significantly different in the two groups (acute ischemic--0.111 +/- .033 mumol/mg, ischemic conditions--0.097 +/- .026 mumol/mg, P < 0.20). CONCLUSIONS: In this rodent model of partial gastric devascularization, ischemic conditioning (delay phenomenon) ameliorated the harmful effect of ischemic on esophagogastric anastomotic wound healing

Spin-lattice relaxation in the rotating frame (T1rho) dispersion spectroscopy and imaging were used to study normal and enzymatically degraded bovine articular cartilage. Normal specimens demonstrate significant T1rho "dispersion" (approximately 60 to approximately 130 ms) in the 100 Hz to 9 kHz frequency range. Proteoglycan-degraded specimens have 33% greater T1rho values than collagen-degraded or normal samples. T1rho-weighted images reveal structure not found in conventional T1- or T2-weighted images. Our results suggest that T1rho measurements are selectively sensitive to proteoglycan content. The potential of this method in distinguishing the early degenerative changes in cartilage associated with osteoarthritis is discussed.