Simultaneous cross-evaluation of heterogeneous E. coli datasets via mechanistic simulation.

The extensive heterogeneity of biological data poses challenges to analysis and interpretation. Construction of a large-scale mechanistic model of Escherichia coli enabled us to integrate and cross-evaluate a massive, heterogeneous dataset based on measurements reported by various groups over decades. We identified inconsistencies with functional consequences across the data, including that the total output of the ribosomes and RNA polymerases described by data are not sufficient for a cell to reproduce measured doubling times, that measured metabolic parameters are neither fully compatible with each other nor with overall growth, and that essential proteins are absent during the cell cycle-and the cell is robust to this absence. Finally, considering these data as a whole leads to successful predictions of new experimental outcomes, in this case protein half-lives.

Combinatorial processing of bacterial and host-derived innate immune stimuli at the single-cell level.

During the course of a bacterial infection, cells are exposed simultaneously to a range of bacterial and host factors, which converge on the central transcription factor nuclear factor (NF)-κB. How do single cells integrate and process these converging stimuli? Here we tackle the question of how cells process combinatorial signals by making quantitative single-cell measurements of the NF-κB response to combinations of bacterial lipopolysaccharide and the stress cytokine tumor necrosis factor. We found that cells encode the presence of both stimuli via the dynamics of NF-κB nuclear translocation in individual cells, suggesting the integration of NF-κB activity for these stimuli occurs at the molecular and pathway level. However, the gene expression and cytokine secretion response to combinatorial stimuli were more complex, suggesting that other factors in addition to NF-κB contribute to signal integration at downstream layers of the response. Taken together, our results support the theory that during innate immune threat assessment, a pathogen recognized as both foreign and harmful will recruit an enhanced immune response. Our work highlights the remarkable capacity of individual cells to process multiple input signals and suggests that a deeper understanding of signal integration mechanisms will facilitate efforts to control dysregulated immune responses.

Tornwaldt's cyst: incidence and a case report.

Tornwaldt's cyst is an uncommon type of nasopharyngeal cyst that may cause clinically significant symptoms. We reviewed reports of 31,855 computed tomography (CT) scans and 21,158 magnetic resonance imaging (MRI) scans to ascertain how many Tornwaldt's cysts were discovered incidentally. These images had been obtained between Jan. 1, 1994, and Dec. 31, 1999, at the University of Virginia Health Sciences Center. We found that 32 Tornwaldt's cysts had been incidentally detected in 20 women and 12 men. Four of these cysts had been found on CT (0.013%; mean size: 0.66 cm3) and 28 on MRI (0.13%; mean size: 0.58 cm3). The overall rate was 0.06% (32/53,013). The most common indications for imaging in these patients were headache, seizures, dizziness/vertigo, and pharyngeal symptoms. We also report the case of a patient with a symptomatic Tornwaldt's cyst whose symptoms resolved after treatment with endoscopic marsupialization. Tornwaldt's cyst should be remembered as an uncommon but potentially treatable cause of many symptoms seen in a typical otolaryngology practice.

Cochlear implantation in patients with auditory neuropathy of varied etiologies.

OBJECTIVES/HYPOTHESIS: Auditory neuropathy is a relatively recently described pattern of hearing loss characterized by preservation of outer hair cell function despite absent brainstem auditory evoked responses. Intact outer hair cell function is demonstrated by the presence of otoacoustic emissions and/or a measurable cochlear microphonic on electrocochleography, whereas no synchronous neural activity (absent action potentials) is seen on acoustically evoked brainstem auditory evoked response testing. The study reviews the authors' experience with six patients diagnosed with auditory neuropathy, four of whom have undergone cochlear implantation. MATERIALS AND METHODS: A retrospective review of all medical and audiological charts at the University of Virginia Hospitals (Charlottesville, VA) was performed to identify patients who have undergone cochlear implantation or have been diagnosed with auditory neuropathy, or both. RESULTS: Six patients with hearing loss attributable to auditory neuropathy were identified, four of whom have undergone cochlear implantation. Causes varied, including congenital, infectious, and idiopathic origins. Adults demonstrated subjective auditory perception on promontory stimulation, whereas no repeatable brainstem auditory evoked response waveforms could be demonstrated on pediatric promontory stimulation testing. Patients with implants demonstrated implant-evoked brainstem auditory evoked responses and improved audiological performance. CONCLUSIONS: The six cases presented in the study represent varied causes and, probably, varied sites of lesions of auditory neuropathy. Promontory stimulation has been valuable, particularly in adults. Cochlear implantation allows the opportunity to provide a supraphysiological electrical stimulation to the auditory nerve, with the hope of reintroducing synchronous neural activity. Greater confidence and enthusiasm for cochlear implantation in appropriately selected patients with auditory neuropathy are gained through experience with such diverse cases.

Otogenic sigmoid sinus thrombosis: what is the role of anticoagulation?

OBJECTIVES: The treatment of otogenic sigmoid sinus thrombosis with surgery and antibiotics is well established. However, the role of anticoagulation remains unstudied. The study reviews the signs, symptoms, radiological evaluation, surgical treatment, and medical management of patients with otogenic sigmoid sinus thrombosis treated with or without anticoagulation. STUDY DESIGN: Retrospective review of nine patients from 1995 to 2001 with sigmoid sinus thrombosis. METHODS: Patients were identified by a review of all medical and radiological records. Signs, symptoms, diagnostic studies, treatments, and outcomes were recorded. In addition, telephone follow-up was performed. RESULTS Nine patients were identified over a 6-year period from 1995 to 2001. Patients had a mean follow-up time of 9 months (range, 1-24 mo). Of the nine patients identified, eight patients (89%) had tympanostomy tube placement, six patients (67%) had canal wall intact mastoidectomy, and one patient (11%) had canal wall down mastoidectomy. Needle aspiration of the sinus was performed in four of nine patients (44%), and incision of the sinus in two of nine (22%). Treatment with broad-spectrum antibiotics occurred in all patients with a mean duration of 12 days (range, 2-22 d) intravenously and 7 days (range, 0-21 d) orally. Sixty-seven percent of patients (six of nine) were anticoagulated: Five patients received low-molecular-weight heparin, and one patient received heparin-coumadin. No mortality occurred in either the anticoagulated or non-anticoagulated group. One anticoagulated patient did have persistent headaches and otorrhea. CONCLUSIONS: Surgery and antibiotic therapy are the cornerstones of the management of otogenic sigmoid sinus thrombosis. However, the role of anticoagulation remains unclear. Because complications of embolization and persistent sepsis are low in otogenic sigmoid sinus thrombosis patients treated with or without anticoagulation, withholding anticoagulation in selected patients is reasonable. Serial imaging to monitor for thrombus progression is advisable.

Pitfalls in the endoscopic drainage of subperiosteal orbital abscesses secondary to sinusitis.

OBJECTIVE: To review the safety and efficacy of endoscopic drainage of subperiosteal orbital abscesses (SPOAs) secondary to sinusitis and to evaluate risk factors that may be associated with failure. STUDY DESIGN: Retrospective chart review. METHODS: All patients admitted to the University of the Virginia Health System with a diagnosis of SPOA between 1992 and 1999 were reviewed. RESULTS: Seven of the 10 SPOAs identified, each located medially, resolved without complication after endoscopic drainage. The remaining three patients required a second drainage. One patient had an inferiorly located SPOA, which recurred laterally after endoscopic drainage. A second pediatric patient, who did not undergo a routine second-look procedure, developed middle turbinate lateralization and synechiae, which led to recurrent SPOAs. A third patient with a significant history of sinusitis was found to have an ethmoid sinus mucocele extending into the medial and posterior orbit. All patients eventually resolved their symptoms. CONCLUSIONS: Endoscopic drainage of medial SPOAs appears to be safe and effective. However, several risk factors must be recognized when present. Management of these risk factors is discussed.