Faculty Bibliography

OBJECTIVES/OBJECTIVE:To report recurrent uveitis as a manifestation of poststreptococcal syndrome and discuss a role of adenotonsillectomy as a treatment option. STUDY DESIGN/METHODS:Case study. METHODS:A case report of a 6-year-old, otherwise healthy girl with group A streptococcal uveitis managed successfully with adenotonsillectomy. RESULTS:In the year after surgery there were only two episodes of uveitis, contrasted with a preoperative 3-year history of 8 to 10 annual episodes despite corticosteroid therapy. Moreover, as a result of the postoperative improvement the child was able to avoid impending methotrexate therapy. CONCLUSIONS:Although the role of tonsillectomy in managing poststreptococcal uveitis is unknown, our results suggest a positive impact independent of the baseline tonsillitis frequency. Otolaryngologists should be aware of these uncommon sequelae of streptococcal infection and the potential role of tonsillectomy in treatment.

Escherichia coli grows over a wide range of pHs (pH 4.4 to 9.2), and its own metabolism shifts the external pH toward either extreme, depending on available nutrients and electron acceptors. Responses to pH values across the growth range were examined through two-dimensional electrophoresis (2-D gels) of the proteome and through lac gene fusions. Strain W3110 was grown to early log phase in complex broth buffered at pH 4.9, 6.0, 8.0, or 9.1. 2-D gel analysis revealed the pH dependence of 19 proteins not previously known to be pH dependent. At low pH, several acetate-induced proteins were elevated (LuxS, Tpx, and YfiD), whereas acetate-repressed proteins were lowered (Pta, TnaA, DksA, AroK, and MalE). These responses could be mediated by the reuptake of acetate driven by changes in pH. The amplified proton gradient could also be responsible for the acid induction of the tricarboxylic acid (TCA) enzymes SucB and SucC. In addition to the autoinducer LuxS, low pH induced another potential autoinducer component, the LuxH homolog RibB. pH modulated the expression of several periplasmic and outer membrane proteins: acid induced YcdO and YdiY; base induced OmpA, MalE, and YceI; and either acid or base induced OmpX relative to pH 7. Two pH-dependent periplasmic proteins were redox modulators: Tpx (acid-induced) and DsbA (base-induced). The locus alx, induced in extreme base, was identified as ygjT, whose product is a putative membrane-bound redox modulator. The cytoplasmic superoxide stress protein SodB was induced by acid, possibly in response to increased iron solubility. High pH induced amino acid metabolic enzymes (TnaA and CysK) as well as lac fusions to the genes encoding AstD and GabT. These enzymes participate in arginine and glutamate catabolic pathways that channel carbon into acids instead of producing alkaline amines. Overall, these data are consistent with a model in which E. coli modulates multiple transporters and pathways of amino acid consumption so as to minimize the shift of its external pH toward either acidic or alkaline extreme.

To enable stratification and barrier function, the epidermis must permit self-renewal while maintaining adhesive connections. By generating K14-GFP-actin mice to monitor actin dynamics in cultured primary keratinocytes, we uncovered a role for the actin cytoskeleton in establishing cellular organization. During epidermal sheet formation, a polarized network of nascent intercellular junctions and radial actin cables assemble in the apical plane of the monolayer. These actin fibers anchor to a central actin-myosin network, creating a tension-based plane of cytoskeleton across the apical surface of the sheet. Movement of the sheet surface relative to its base expands the zone of intercellular overlap, catalyzing new sites for nascent intercellular junctions. This polarized cytoskeleton is dependent upon alpha-catenin, Rho, and Rock, and its regulation may be important for wound healing and/or stratification, where coordinated tissue movements are involved.

A method is presented for analyzing cochlear implant stimulations and typical representations used in simulations. Filtered "white-noise" bands are modulated using sinusoids, representing differing stimulation channels. These representations, along with their corresponding envelopes, are used to generate neural activation patterns (NAPs), which represent "normal-hearing" responses in the auditory nerve to these stimuli. Additionally, NAPs are generated to represent the neural activity induced by cochlear implant stimulation strategies, assuming exponential rolloff from the electrodes. The mean squared error is measured between NAPs both directly, and after compensation for perceptual resolution. Results suggest that the noise-band approximation of the CIS implant signal actually has more in common with the original source than with the implant stimulation patterns.

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.

Interleukin 2 (IL-2) and interleukin 12 (IL-12) have potent anti-tumour activity as single agent therapy against several different murine and human tumours. Combining these cytokines may result in improved therapeutic effectiveness, however, the toxicity associated with simultaneous administration is prohibitive. This study was designed to determine the specific histopathologic changes associated with combination therapy. Mice were treated with 5 days of interleukin-2, interleukin-12, or both using standard doses and schedules. Histologic specimens were prepared from all internal organs on a daily basis to identify specific pathologic abnormalities. Treatment with interleukin-2, interleukin-12, or both resulted in pathologic insult to the liver and gastrointestinal tract. Mild lymphoplasmacytic infiltrates were seen in the liver. The most significant pathology was seen in the large bowel and consisted of apoptosis of colonic epithelial cells. While recovery of injured gastrointestinal mucosa occurred in mice treated with interleukin-2 or interleukin-12 alone, combination therapy resulted in death before recovery was possible. Combination interleukin-2 and interleukin-12 therapy results in irreversible injury of the colon as manifested by increased epithelial cell apoptosis and death in mice. Understanding the pathologic changes associated with combination cytokine therapy may lead to strategies that prevent toxicity while maintaining therapeutic effects.

The middle vault is a transition zone between the nasal tip and nasal bones and plays an important role in profile, tip projection, tip rotation, and tip support. This report presents an alternative to conventional techniques specific to the middle nasal vault for a patient population with particular nasal features. A narrow middle vault with internal nasal valve collapse is functionally and aesthetically addressed by the insertion of spreader grafts. However, the inverse of this situation is sometimes encountered. A patient with a broad middle vault and without internal nasal valve collapse will benefit from reduction of the horizontal width of the cartilaginous dorsum, which is in effect the reverse of spreader grafts. This effect is achieved by excising a vertical wedge-shaped strip of cartilage that follows the length of the upper lateral cartilage at the junction of the upper lateral cartilage and the dorsal nasal septum.

IL-13 potently stimulates eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung, effects that depend on the induction of various matrix metalloproteinases (MMPs). Here, we compared the remodeling and inflammatory effects of an IL-13 transgene in lungs of wild-type, MMP-9-deficient, or MMP-12-deficient mice. IL-13-induced alveolar enlargement, lung enlargement, compliance alterations, and respiratory failure and death were markedly decreased in the absence of MMP-9 or MMP-12. Moreover, IL-13 potently induced MMPs-2, -12, -13, and -14 in the absence of MMP-9, while induction of MMPs-2, -9, -13, and -14 by IL-13 was diminished in the absence of MMP-12. A deficiency in MMP-9 did not alter eosinophil, macrophage, or lymphocyte recovery, but increased the recovery of total leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluids from IL-13 transgenic mice. In contrast, a deficiency in MMP-12 decreased the recovery of leukocytes, eosinophils, and macrophages, but not lymphocytes or neutrophils. These studies demonstrate that IL-13 acts via MMPs-9 and -12 to induce alveolar remodeling, respiratory failure, and death and that IL-13 induction of MMPs-2, -9, -13, and -14 is mediated at least partially by an MMP-12-dependent pathway. The also demonstrate that MMPs-9 and -12 play different roles in the generation of IL-13-induced inflammation, with MMP-9 inhibiting neutrophil accumulation and MMP-12 contributing to the accumulation of eosinophils and macrophages.

OBJECTIVES: Cyclooxygenases (COX) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. COX-2, unlike the constitutively expressed COX-1, is an inducible enzyme upregulated during cell proliferation and inflammation. More recently, COX-2 has been implicated in the development of numerous types of epithelial cancers. In addition, COX-2 is highly expressed in several inflammatory diseases. Because of its dual role in inflammation and cancer, we were interested in determining if COX-2 plays a role in the development of human thyroid carcinoma and Hashimoto's thyroiditis, an autoimmune condition frequently associated with thyroid malignancy. MATERIALS AND METHODS: Twenty paraffin-embedded human tissue specimens, including normal, inflammatory, and neoplastic thyroid sections, were analyzed by immunohistochemical staining for expression of human COX-2. In addition, COX-2 protein expression was verified by Western blot in two specimens. RESULTS: Immunohistochemical staining confirmed the presence of COX-2 in thyroid epithelial neoplasms, including papillary and follicular carcinomas. Moreover, COX-2 expression was observed in patients with Hashimoto's thyroiditis. COX-2 expression, however, was not observed in normal thyroid tissue, multinodular goiter, or anaplastic carcinoma. CONCLUSIONS: We have shown that cyclooxygenase-2 is expressed in thyroid carcinoma and thyroid epithelium from patients with Hashimoto's thyroiditis but not in normal thyroid. The expression of COX-2 in both of these thyroid pathologies may provide a basis for the relationship between carcinogenesis and autoimmunity.