Paul O. Dutcher

Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus.

Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE). However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE.

Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks

Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38+ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells.

New imaging techniques in diagnosis of cerebrospinal fluid fistula

The localization of a cerebrospinal fluid fistula producing cerebrospinal fluid otorrhea can be very difficult. However, the exact anatomic localization of the bony defect is important when selecting the surgical approach to repair. Case reports of two patients in whom spontaneous cerebrospinal fluid otorrhea occurred following pressure equalization tube placement for middle‐ear effusion are presented. Nuclear magnetic imaging supplemented CT scan findings, providing noninvasive localization of the defect. Preoperative impressions were confirmed at surgery. In addition to discussing the use of magnetic resonance imaging in evaluating cerebrospinal fluid otorrhea, the literature will also be reviewed.

The prevalence and clinical course of patients with ‘incidental’ acoustic neuromas

Conclusions. This study suggests that among patients diagnosed with ‘incidental’ acoustic neuromas (ANs), a substantial portion are discovered incidentally. Small and medium-sized ANs that are found incidentally may have a more benign nature, and may be less likely to require interventions. Objective. To estimate the prevalence of ANs, and to compare the prognosis and progression of the disease between those diagnosed incidentally verse symptomatically with an AN. Patients and methods. This was a retrospective evidence-based case series of patients with AN treated at a tertiary medical center between November 1999 and January 2005. An MRI with gadolinium was performed on all patients to establish the diagnosis of AN. A medical chart review of these patients was searched for sex distribution, age, presenting symptoms, hearing loss, speech discrimination scores, tumor characteristics by imaging, intervention performed, and time between diagnosis and intervention. The studied population was divided into those patients with pre-imaging audiovestibular symptoms provoking a clinical suspicion of AN (symptomatic group) and those without a pre-imaging suspicion of AN (incidental group). Results. The charts of 120patients with ANs were analyzed and categorized as either incidentally or symptomatically discovered. Incidentally discovered ANs accounted for 12% of patients with the diagnosis of AN in our population. The average age at diagnosis was 55.7 and 52.8years (p=0.50) in the symptomatic and incidental groups, respectively. The gender distribution was not different between the groups (p=0.08). Audiometry revealed a speech discrimination score asymmetry greater in the symptomatic group (p<0.0001). Tumor size by imaging performed at diagnosis in the incidental population was 1.09cm on average, compared with 1.5cm in the symptomatic patients (p=0.08). A greater proportion of patients with symptomatically discovered AN underwent intervention by surgical resection, stereotactic radiosurgery, or radiation compared with patients with incidentally discovered AN (76% versus 47%, p=0.02).

The safety and efficacy of bedside tracheotomy.

Many institutions require that tracheotomies be performed in the operating room. Movement of critically ill patients dependent on multiple life support systems is technically difficult, labor intensive, and potentially dangerous for the patients. Between 1983 and 1992, 1088 tracheotomies were performed on patients ages 1 week to 94 years at the University of Rochester affiliated hospitals on critically ill patients as isolated procedures. The procedure was performed in the Intensive Care Units (ICU) on 996 patients, (92.9%), whereas 92 patients (7.1%) had tracheotomies in the operating room (OR1). An additional 346 tracheotomies took place in the operating room in conjunction with other head and neck procedures (OR2). Incidence of perioperative bleeding (within 48 hours) was 2.3% in the ICU group, 2.1% in the ORI group, and 2.0% in the OR2 group. Incidence of stomal infection was also similar among the three groups at 1.8%, 2.1%, and 1.5%, respectively. Tube dislodgement in all groups was a complication. No statistical differences were noted among the three groups (ICU, OR1, OR2) at the p < 0.01 level. Criteria for performing the tracheotomy in the ICU are delineated and discussed.

Gadolinium‐DTPA‐Enhanced magnetic resonance scanning in cerebellopontine angle tumors

Magnetic resonance (MR) imaging has quickly emerged and already replaced computerized tomography (CT) in the evaluation of cerebellopontine angle (CPA) lesions, although even MR scanning may occasionally yield equivocal results. We recently studied six patients with a new MR image‐enhancing contrast, gado‐linium‐DTPA (Gd‐DTPA). All patients were suspected of having CPA pathology, and the standard MR scan was either negative, equivocal, or left unanswered questions regarding confirmed lesions. The Gd‐DTPA‐enhanced MR scan confirmed tumors or added useful information in five of six patients.

Exploratory tympanotomy revealing incus discontinuity and stapedial otosclerosis as a cause of conductive hearing loss.

Objective: To describe a unilateral progressive conductive hearing loss caused by incus discontinuity (without erosion of the long process of the incus), and otosclerosis with fixation of the stapedial footplate. Study Design: Case report. Setting: Department of Otolaryngology, Head and Neck Surgery of the University of Rochester Medical Center, which is a regional tertiary referral center. Patient: A 54-year-old woman with multiple otologic complaints including tympanic membrane perforations, otalgia, tinnitus, and hearing loss. Audiography demonstrated 100% speech discrimination bilaterally and a significant conductive right-sided hearing loss. Intervention: The patient underwent a stapedectomy, during which a discontinuity between the long process of the incus and the stapes with no bony erosion was identified. The stapedectomy was completed and an ossicular piston prosthesis was inserted to reestablish ossicular continuity with the tympanic membrane. Main Outcome Measure: Improved subjective hearing confirmed objectively by audiography. Conclusion: This is the third reported case of an unusual combination of otosclerosis and ossicular discontinuity, and the first such case report in a patient without head trauma. In addition, it adds a unique item to the differential diagnosis of the pathologic features implicated in an ear with a conductive deficit and normal tympanogram.

R162: Langerhans Cell Histiocytosis: Case Series

from nitinol wire. Various metal tubes and instruments were used for stent deployment development. Rigid pediatric bronchoscopes were selected because they faciliated (1) ventilation, (2) endoscopic visualization with a telescope, (3) stent deployment, (4) suctioning, and (5) manipulation of a side-firing laser fiber. Ex vivo dosimetry experiments using a 1450nm diode laser provided reasonable settings which would reshape tissue without ablation. Five rabbits underwent stent deployment and laser irradiation at varying dosimetry parameters. The rabbits were euthanized and the trachea removed after 12 weeks to allow adequate wound healing in the mechanically deformed state. Light microscopy, confocal imaging with viability dyes, and mechanical analysis were performed. RESULTS: Instrumentation development for use in the rabbit model is a technical challenge, and necessitated the use of pediatric airway equipment. The stent produced minimal gross inflammatory reaction and could be tolerated. The relationship between histology, viability, and mechanical properties will be discussed. CONCLUSION: An endoscopic delivery system combining short-term stenting and laser cartilage reshaping was evaluated in an in vivo rabbit model. Dosimetry settings for a 1450nm diode laser were determined with regard to tissue damage and cartilage deformity. SIGNIFICANCE: The present concept incorporating stenting and laser cartilage reshaping technology may have application in the endoscopic treatment of tracheal deformities. SUPPORT: NIH (D00170,DC005572,RR-01192) Air Force Office of Scientific Research (FA9550-04-1-0101).