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Objective: Porcine-derived small intestine submucosa (SIS) extracellular matrix (ECM) surgical patches claim to have greater regenerative properties compared with dermal extracellular matrices. We hypothesized that using SIS-ECM in a bioengineered composite tracheal graft would allow better incorporation into the native tissue., Methods: Two types of size-matched polycaprolactone support scaffolds were designed: rigid and flexible. The SIS-ECM was wrapped around the polycaprolactone supports lining the inside and outside of the graft. The grafts were implanted in 4 Yorkshire pigs, replacing an ∼2 cm segment of native trachea. Airway patency was evaluated with computed tomography scans and explanted grafts were examined grossly and histologically., Results: All animals survived through the immediate postoperative period. Generally, extraluminal examination showed a smooth transition between native and graft without significant volumetric loss. Animals that received the flexible design survived ∼10 days longer than those that received the rigid design; however, severe perianastomotic intraluminal granulation tissue was observed. The rigid design had less significant intraluminal granulation tissue development at the distal anastomosis, but partial dehiscence had occurred at the proximal anastomosis interrupting graft incorporation., Conclusions: The generally good extraluminal graft incorporation in our composite tracheal graft highlights some increased regenerative capabilities of SIS-ECM. However, the presence of intraluminal granulation tissue indicates that its use as an off-the-shelf, unaltered substrate in an airway graft is still not ideal. Further research must be conducted to determine whether a modification of the substrate is possible to enhance luminal airway incorporation and to exert control over the mechanisms responsible for granulation tissue development., (© 2020 The Authors.)

Objectives: Relapsing polychondritis is a rare, multi-systemic and inflammatory condition of unknown origin. We currently lack a core set of measures to assess and follow damage in patients suffering from this condition. Our primary aim was to derive a disease-specific damage measuring tool for relapsing polychondritis, the Relapsing Polychondritis Damage Index (RPDAM)., Methods: We performed an international 4-round multicenter Delphi study during which experts were asked to rate the relevance of potential damage items for relapsing polychondritis (141 items were obtained from a literature review and 12 from expert suggestion), using a Likert Scale. The selection of items for each subsequent round was based on the median rating of each item., Results: Twenty-four experts from 11 nationalities participated in round 1 and 22 in rounds 2, 3 and 4. From the initial 153 potential damage items, 44 items were selected during round 1, 30 items during round 2 and 16 during round 3. During round 4, we refined the index to a total of 17 items referring to ear nose and throat, eye, respiratory, cardiovascular and hematological systems as well as to treatment-related specific damage items., Conclusion: We have developed by international consensus a scoring system to assess damage in patients with relapsing polychondritis. Following its validation, the RPDAM may contribute to improve the care of patients suffering from this rare condition as well as to standardize data collection for future clinical trials., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background: We aimed to develop a process using three-dimensional (3D) printing to create bioengineered tracheal grafts (BETGs) for reconstruction of anterior tracheal defects in a large-animal model (porcine) that would have translational relevance for potential human use., Methods: Preoperative computed tomographic scans were used to create virtual 3D models of the animal airways. Anatomically scaled tracheal grafts were subsequently developed using 3D-printed polycaprolactone and extracellular matrix. A 4-cm anterior tracheal defect (about 50% of the length of the subject trachea) was surgically created in 4-week-old female Yorkshire pigs and reconstructed using the customized grafts. Gross and microscopic analyses of the grafts were performed., Results: The BETGs were implanted in 7 animals. There was adequate graft-native trachea size match at the operation. The trachea was successfully reconstructed in all cases. Gross examination at autopsy showed a structurally intact, well-incorporated graft. Histologic evaluation showed respiratory mucosal coverage and vascularity of the graft. Five of 7 animals outlived the 3-month study period. The animals had approximately 100% growth during the study period., Conclusions: We report of a 3D-printed BETG to repair long-segment anterior tracheal defects in a large-animal model. Although the study duration is short, this work presents an efficient strategy for tracheal graft bioengineering with potential translational relevance for human use., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the presentation and clinical course of subglottic stenosis (SGS), in particular the development of concurrent airway lesions, in patients with Granulomatosis with Polyangiitis (Wegener's) (GPA)., Materials and Methods: Retrospective review of clinical data from all patients presenting to our institution from 2000 to 2012 with SGS and GPA., Results: Thirty-five patients were identified. The average age at diagnosis was 33 years old. Eleven patients (31%) presented with SGS as part their initial manifestation of GPA. The remaining patients developed SGS later, at a median of 2.5 years from diagnosis (range 6 months to 14 years). Twelve patients (34%) were noted to have multilevel airway involvement. Seven patients (20%) had documentation of cricoarytenoid joint fixation and vocal cord immobility. This was typically progressive in nature and occurred at an average of two years following the diagnosis of SGS. Six patients (17%) had mid/distal tracheal stenosis and four (11%) had bronchial stenosis. The majority of patients (86%) had evidence of concurrent sinonasal involvement, ten patients (29%) had evidence of otologic involvement and eight (23%) had ocular involvement., Conclusions: Cricoarytenoid joint fixation and distal stenosis occur not infrequently in patients with GPA and SGS, resulting in progressive multilevel airway stenosis in about one third of patients. It is critical to identify multilevel stenosis when managing the airways of these patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The rarity of relapsing polychondritis (RP) has hindered the development of standardized tools for clinical assessment. Here, we describe the development of a preliminary score for disease assessing activity in RP, the Relapsing Polychondritis Disease Activity Index (RPDAI)., Methods: Twenty-seven RP experts participated in an international collaboration. Selection and definition of items for disease activity were established by consensus during a 4-round internet-based Delphi survey. Twenty-six experts assessed the Physician's Global Assessment (PGA) of disease activity on 43 test cases on a 0-100 scale, yielding a total of 1118 PGA ratings. The weight of each item was estimated by multivariate regression models with generalized estimating equation, using PGA as the dependent variable., Results: Experts decided in consensus that the RPDAI should consider the 28-day period before each RPDAI assessment. Inter-rater reliability assessed by the intra-class correlation coefficient for the 1118 PGA ratings was 0.51 (CI95%: 0.41-0.64). The final RPDAI score comprised 27 items with individual weights ranging from 1 to 24 and a maximum theoretical RPDAI score of 265. Correlation between the RPDAI scores calculated based on the weights derived from the final multivariate model, and the 1118 PGA ratings was good (r=0.56, p<0.0001)., Conclusion: We have developed the first consensus scoring system to measure disease activity in relapsing polychondritis (see www.RPDAI.org for online scoring). This tool will be valuable for improving the care of patients with this rare disease., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: Laryngotracheal involvement in relapsing polychondritis (RP) is rare. However, it is one of the most common causes of death in this patient population. We present three patients who primarily presented with laryngeal manifestations of RP and a novel treatment option for bamboo nodules., Study Design: Retrospective chart review and comprehensive review of the literature., Results: Two patients first presented to an otolaryngologist because of hoarseness and chronic cough that eventually progressed to dyspnea upon exertion. Laryngeal examination revealed subglottic stenoses. Upon rheumatologic workup both were diagnosed with RP. After treatment with steroids and immunosuppressive drugs, one of the patient's laryngeal symptoms improved, whereas the other required dilation procedures. Neither patient had classic auricular or nasal symptoms upon initial presentation. The third patient was being treated for spasmodic dysphonia and was noted to have bamboo nodules with accompanying dysphonia. Rheumatologic workup revealed RP and systemic treatment ensued. Unfortunately, her symptoms of hoarseness persisted despite systemic treatment. A pulsed-potassium-titanyl-phosphate (KTP) laser was applied to the bilateral bamboo nodules, which eventually caused resolution of her vocal fold lesions and dysphonia., Conclusions: We present three patients with RP, all of whom sought health care by an otolaryngologist primarily. Awareness of this disease entity and the possibility for early laryngeal involvement is crucial for proper care of those with this life-threatening disease., (Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Objectives: Locally advanced cancers of the head and neck require aggressive treatment, often with limited effectiveness and significant toxicity and morbidity. This pilot study was designed to assess tolerance using combined hyperfractionated radiotherapy and the halogenated pyrimidine radiosensitizer 5'-iododeoxyuridine (IdUrd)., Study Design: This was a prospective single-arm study open to patients with advanced head and neck cancers that had a poor chance of control with conventional radiation therapy. Patients were treated with hyperfractionated radiation therapy at standard doses in combination with an IdUrd infusion and observed for tumor response and normal tissue tolerances., Methods: Radiation therapy was delivered in fractions of 1.2 Gy or 1.5 Gy twice daily to a total dose in the range of 70 to 76 Gy. IdUrd was delivered as an intravenous infusion (1000 mg/m2 per day) for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy., Results: Twelve patients with advanced squamous cell lesions were enrolled and 11 were observed to have complete clinical remissions. Seven patients remained clinically free of local disease at the time of death or most recent follow-up. Acute toxicities, usually hematologic or mucosal, were severe and all patients required treatment modifications and considerable supportive care., Conclusions: Although a high rate of response was achieved using this regimen, the toxicities are prohibitive. The kinetic profile of IdUrd incorporation suggests the need for future studies using repetitive short courses of IdUrd.

Objectives: Isolated reports suggest a possible association of endolymphatic sac tumors (ELSTs), which are extremely rare in the general population, with von Hippel-Lindau disease (VHL). To determine if hearing loss and ELSTs are a component of VHL, we examined prevalence, clinical presentation, and natural history of hearing loss and ELSTs in VHL., Design: Brain magnetic resonance images (MRIs) from 374 patients screened for VHL were reviewed for evidence of ELSTs. The VHL patients with MRI evidence suggestive of ELSTs or a history of hearing loss, tinnitus, or vertigo underwent additional radiologic and audiologic evaluations. To further assess prevalence of hearing loss and ELST in VHL, the next 66 patients screened in the VHL clinic (49 with proven VHL, 17 at risk for VHL) received MRI and audiologic assessment., Setting: Referral center., Participants: Study subjects comprised 374 persons screened for VHL, 66 consecutive patients with VHL or at risk for VHL, 4 patients with 6 ELSTs, and 13 previously reported patients with VHL and invasive tumors of the temporal bone., Intervention: Magnetic resonance image and computed tomographic (CT) scan of the posterior fossa and audiologic assessment., Main Outcome Measures: Any ELST visible on MRI or CT and hearing loss compatible with ELST., Results: Magnetic resonance imaging revealed evidence of 15 ELSTs in 13 (11%) of 121 patients with VHL, but in none of the 253 patients without evidence of VHL (P<.001). Clinical findings in these 13 patients included hearing loss (13), tinnitus (12), vertigo (8), and facial paresis (1). Mean age at onset of hearing loss was 22 years (range, 12-50 years). Hearing for pure tones was abnormal in all affected ears and in 6 of the 11 additional, allegedly unaffected ears. In 8 patients (62%), hearing loss was the first manifestation of VHL. Presence or absence of hearing loss was associated with duration of symptoms (P<.002) and with tumor size (P<.01). Further, 43 (65%) of the 66 patients from the VHL clinic had pure tone threshold abnormalities, abnormalities that occurred bilaterally in 23 (54%) of the 43 affected subjects; however, evidence is lacking for a definitive association with ELST (3 [6%] of 49 patients with proven VHL had ELST evident on MRI)., Conclusions: Hearing loss and ELSTs are frequently associated with VHL syndrome and should be considered when screening individuals at risk for VHL and when monitoring patients with an established diagnosis of VHL. Many patients with VHL have hearing loss without radiographic evidence of an ELST. Whether it is caused by an ELST that is too small to be detected by MRI or is produced by some other etiology is still unknown. Audiologic evaluation and MRI should allow early detection and enhance management of hearing loss in these patients.

Olfactory neuroepithelial cells (ONC) grown from biopsies of human donors are a novel cell culture system that may facilitate studies into normal and disease-related human neurobiology. We further characterized the expression of cell surface markers and intermediate filaments, and responses to neurotrophic factors by ONC. ONC are positive for cell surface markers N-CAM, PSA-N-CAM, neutral endopeptidase, N-aminopeptidase, NGF low-affinity receptor homologue (CD40), and transferrin receptor by flow cytometry for the intermediate filament proteins peripherin, vimentin, and NF-H by immunocytochemistry. Responses to neurotrophic factors measured were process outgrowth, cytoskeletal protein expression, and protein phosphorylation. Process outgrowth was increased by interleukin-beta 164-171 (IL-1beta) or by the combination of IL-1beta, interleukin-6 (IL-6), nerve growth factor (NGF), and basic fibroblast growth factor (bFGF). This combination of IL-1beta, IL-6, NGF, and bFGF (16NF) increased expression of two cytoskeletal proteins, NF-H protein and microtubule-associated protein tau. Application of the individual neurotrophic factors IL-1beta, IL-6, NGF, and bFGF increased protein phosphorylation, while 16NF produced an immediate increase in tyrosine phosphorylation of several proteins (MW of 40-80, 120, 150, and 190 kDa). The 16NF combination appears to act through a tyrosine-kinase-mediated pathway to induce process extension and increase NF-H expression. The ONC culture has the potential to be further explored to examine the relationship among process outgrowth, protein phosphorylation, and synergy between neurotrophin and cytokine receptor systems.

Objective: To determine the clinical features and optimal treatment of subglottic stenosis (SGS) in patients with-Wegener's granulomatosis (WG)., Methods: Review of 43 patients with SGS and treatment of 20 patients with intratracheal dilation-glucocorticoid injection therapy., Results: SGS developed in 43 of 189 patients with WG who were followed up at the National Institutes of Health Clinical Center. The diagnosis of SGS occurred in the absence of other features of active. WG in 21 of 43 patients (49%). In 21 patients (49%), SGS began while the patient was receiving systemic immunosuppressive therapy for disease activity involving other sites. Tracheostomy was required in 10 of 18 patients (56%) who were treated with systemic immunosuppressive therapy. In 20 patients treated with intratracheal therapy, none required tracheostomy and 6 with previous tracheostomies were decannulated., Conclusion: SGS often occurs independently of other features of active WG and is frequently unresponsive to systemic immunosuppressive therapy. Intratracheal dilation-injection therapy provides a safe and effective treatment for WG-associated SGS and, in the absence of major organ disease activity, should be used without concomitant systemic immunosuppressive agents.

Recently, sinusitis has been recognized as a frequent clinical problem in human immunodeficiency virus (HIV-1)-infected individuals. We hypothesized that quantitative defects in immune cells in the nasal mucosa of HIV-positive subjects might mirror those in the peripheral blood and explain a predisposition to sinus disease in this population. Nasal mucosa biopsies were obtained from three different groups of patients-HIV-1 seropositive with sinusitis, HIV-1 seronegative with sinusitis, and HIV-1 seronegative without sinusitis (normal volunteer)-and phenotyped for cluster of differentiation antigen (CD) markers. In this study, we found patients with HIV-1 and sinus disease to have significantly lower numbers of both CD3 and CD4 nasal mucosa lymphocytes than seronegative controls in the nasal mucosa (P < 0.05, P < 0.01, respectively). A correlation between nasal mucosal CD4 cells and peripheral-blood CD4 cells was noted (R = 0.67, P < or = 0.01). No deficiency in the number of nasal mucosa T or TC type mast cells was noted for the HIV-1-positive sinusitis group. Further study is warranted to define more completely the pathophysiology and microbiology of, and therapy for, this important clinical problem.

Background: The halogenated pyrimidines 5'-iododeoxyuridine (IdUrd) and 5'-bromodeoxyuridine (BrdUrd) are under active study as radiation sensitizers for a variety of malignancies. Head and neck neoplasms may also be suitable for halogenated pyrimidine-mediated sensitization; previous regimens using intra-arterial BrdUrd delivery, however, were poorly tolerated., Purpose: A pilot study was undertaken with the use of intravenous IdUrd with hyperfractionated radiotherapy to assess tolerance. In addition, serial tumor biopsy specimens were obtained to determine the kinetics of IdUrd labeling and incorporation., Methods: Twelve patients with squamous cell carcinomas of the head and neck (one patient had stage II cancer, one had stage III, and 10 had stage IV) were treated with hyperfractionated radiation therapy at a dose of 1.2 or 1.5 Gy twice a day, to a total dose in the range of 70-76 Gy. IdUrd (1000 mg/m2 per day) was infused for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy. A tumor biopsy specimen was obtained from 11 patients following initiation of treatment with IdUrd. Eight patients consented to serial biopsy to allow the study of IdUrd-labeling indices and thymidine replacement over time. Incorporation of IdUrd into tumor DNA was determined by high-performance liquid chromatography, and cell labeling was determined with the use of an anti-BrdUrd/IdUrd monoclonal antibody in conjunction with flow cytometry. Patients continue to be followed to assess local control., Results: A plot of corrected IdUrd replacement as a function of infusion time suggests the possibility of a plateau after 5-7 days of infusion at 7.5%-8%. The average rate of replacement from days 1 to 5 was 1.3% per day and was determined by linear regression analysis. Acute toxic effects, especially mucositis, were severe enough to require delays in the radiation therapy. Eleven of 12 patients treated had complete clinical remissions. Seven of these patients remain clinically free of local disease at the time of death or most recent follow-up., Conclusions: The level of IdUrd incorporation and cell labeling should be adequate to produce sensitization. However, the treatment as prescribed in this study (two 14-day infusions of IdUrd during radical radiotherapy with only one planned split) was not completed in a single patient because of either dose-limiting hematologic toxicity or severe mucositis necessitating treatment break. Since this particular regimen is not tolerable, future protocols will have shorter exposures to IdUrd., Implications: Previous regimens using halogenated pyrimidine radiosensitizers have generally used protracted drug delivery schedules. In this study, a high level of IdUrd labeling was measured after 5-7 days of drug infusion. The halogenated pyrimidines deserve further study with the use of repetitive short courses to reduce toxicity and possibly improve efficacy.

Definitive diagnosis of Alzheimer's disease (AD) is made by pathologic examination of postmortem brain tissue in conjunction with a clinical history of dementia. To date, there are no good biological markers for a positive diagnosis of AD in the living patient. In an effort to identify biological markers useful both in the clinical and pathologic diagnosis of AD, we have investigated disease-specific protein alterations in cultured olfactory neurons. Olfactory neurons are readily accessible by biopsy, can be propagated in primary cell culture as olfactory neuroblasts (ONs), and exhibit several elements of AD brain pathophysiology making them powerful tools for the study of AD. Two-dimensional gel analysis of ON proteins from neuropsychologically evaluated AD donors revealed a set of five proteins (Mr 17-50 kD, pI 4.8-6.7) that were significantly altered in concentration when compared to cells from age-matched controls. Further characterization and microsequence analysis could lead to the identification of proteins that may have important diagnostic or therapeutic value in the treatment of AD.

Cell lines of continuously dividing human olfactory neuroblasts can be propagated using olfactory epithelium obtained from human donors at biopsy or autopsy. The expression of neuronal proteins in these cells, such as neurofilament protein and tau protein, can be increased using a combination of factors including nerve growth factor, fibroblast growth factor, interleukin 1 and interleukin 6. These cells also express aspects of human disease. Olfactory neuroblasts generated from donors with the common, sporadic forms of Alzheimer's disease, show elevated levels of the direct precursor to beta-amyloid, the amyloid precursor protein C-terminal derivative (CTD). When treated with the lysosomal inhibitor chloroquine, immunoblots of Alzheimer olfactory neuroblasts show seven-fold higher levels of CTDs than immunoblots from age-matched control neuroblasts. The disease related increases in CTDs can be reversed by treatment with agents that increase intracellular cyclic adenosine monophosphate (cAMP), such as dibutyryl-cyclic-AMP, theophylline, and isoproterenol.

PDT and IUdR-sensitized radiation therapy represent potential advances in the treatment of tumors of the head and neck. Light-activated photosensitizers have definite antitumor activity in both in vitro and in vivo experimental systems. Much of the early clinical work in head and neck cancer involved treatment of patients with advanced, recurrent disease who had not responded to conventional therapy. Because of the limited light penetration in tissue and infiltrative nature of most recurrent lesions, little effective palliation was seen in these advanced cases. More success has been achieved in the treatment of earlier, more superficial lesions, and active investigation continues in this area. Current research is aimed at defining the most appropriate sites and applications for the technique. HpD and DHE are currently only approved for use as investigational compounds in clinical studies. If ongoing trials of PDT in the treatment of superficial bladder cancer, obstructing esophageal cancer, and non-small cell lung cancer show encouraging results, an application will be made to the Food and Drug Administration for approval of DHE as a photosensitizer for general clinical use for these indications. Laboratory work to better understand the mechanism of action of HpD also continues, as well as investigations into alternative photosensitizers with improved tumor localization, less cutaneous photosensitivity, and absorption peaks at deeper penetrating wavelengths of light. A pilot program evaluating IUdR-sensitized radiation therapy for treatment of advanced head and neck cancer is in progress. If encouraging early results continue to be observed, a randomized trial comparing IUdR-sensitized radiation therapy with conventional radiation therapy can be conducted. Hopefully, these developments in the field will improve the therapy for patients with head and neck cancers.

Fluid obtained during myringotomy and tube placement in 20 patients with middle ear effusions was assayed for leukocyte esterase activity using a quantitative spectrophotometric assay. This quantitative assay used the synthetic substrate, N-tosyl indoxyl alaninate. Seven of the 20 samples showed no measurable enzyme activity (8 U/ml or less). The remaining samples demonstrated activity ranging from 20 to 1600 units. Although enzyme activity did not correlate well with the physical appearance of the fluid, it did correlate with clinical history, suggesting the presence of a purulent exudate rather than serous effusion. Leukocyte esterase activity in the fluid appears to hold promise as an indicator for the presence of chronic middle ear infection. The enzyme can be assayed by a simple and fast diagnostic strip test, with results available almost immediately.

We prospectively studied and compared clinical features, treatment, course of illness, and long-term morbidity and mortality rates for Wegener granulomatosis in 23 childhood-onset patients with those of 135 adult-onset patients who were studied concurrently. Treatment was usually provided with glucocorticoids and cyclophosphamide. The mean follow-up period was 8.7 years for childhood-onset and 7.6 years for adult-onset Wegener granulomatosis. Most aspects of Wegener granulomatosis were similar in childhood-onset and adult-onset patients. Permanent morbidity from disease occurred in 86% of both groups. However, some features were significantly different. Wegener granulomatosis in childhood-onset patients was complicated five times more often by subglottic stenosis and twice as often by nasal deformity. Treatment-related permanent morbidity occurred in 22% of childhood-onset patients and 45% of adult-onset patients. After similar periods of cyclophosphamide therapy and follow-up, cyclophosphamide-related malignancies were less likely (0% vs 11%) to have developed in childhood-onset patients. Although 89% of patients treated with glucocorticoids and cyclophosphamide had remission, prolonged delay in achieving remission and relapses led in both patient groups to freedom from active disease for approximately 50% of the total patient-years. As a result, morbidity was substantial and has led to comparative studies of alternative therapies.

Wegener's granulomatosis (WG) is a multisystem inflammatory disease characterized by vasculitis, granuloma formation, and necrosis. Among 158 patients treated at the National Institutes of Health during the past 24 years, 145 (92%) had an otolaryngologic manifestation of their disease and 25 (16%) had subglottic stenosis (SGS). SGS varied from asymptomatic to life-threatening. Sixteen (80%) of 20 patients with fixed SGS required surgical intervention, including manual dilations, carbon-dioxide laser resections, and laryngotracheoplasty (LTP). LTP was performed with and without microvascular reconstruction. Thirteen of the patients required tracheostomy and all 13 were ultimately decannulated. Five patients who repeatedly failed dilations and/or endoscopic laser surgery underwent LTP. Since 1987, two patients have undergone LTP with microvascular free flaps. Both patients were subsequently decannulated. The authors' experience demonstrates that management of SGS in WG is complex, requiring individualized frequent multimodality interventions to achieve satisfactory results. Microvascular laryngotracheal reconstruction should be considered in the surgical armamentarium for patients with persistent stenoses.

The expression of amyloid precursor protein (APP) in olfactory neuroblasts has been examined with a panel of antibodies directed against varied regions of the APP molecule. The pattern of reactivity was compared to that in the transformed human glial cell line SVG, human cortical brain tissue, and in kidney epithelial 293 cells containing stably transfected and overexpressed human APP751. Antibodies directed against the C-terminus and extracellular domains of amyloid precursor protein (APP) react more strongly on immunoblot with transfected 293 cells and brain tissue than with olfactory neuroblasts (ON) or SVG cells. Antibodies directed against the beta/A4 region of APP show a contrasting pattern of reactivity, yielding greater reactivity with ON and SVG cells than with transfected 293 cells or brain tissue. Analysis of the APP transcripts using polymerase chain reaction indicates that ON and SVG both make predominantly APP770 and 751, as does the transfected 293 cell line. In the absence of any differences in APP transcripts among the cell lines, the difference in availability of the beta/A4 region appears likely to be due to posttranslational modification. These data therefore indicate that processing of APP varies among cell lines and thus may vary from tissue to tissue.

We describe the unique clinical and histopathologic features of a child with biochemical and immunocytochemical features of Niemann-Pick disease type C (NPC). Clinically, she was found to have multiple xanthomas of the upper aerodigestive tract with dysphagia and expressive language delay, splenomegaly, bony infarcts, and type IIb hyperlipidemia. Neurologic examination was otherwise normal. Microscopy revealed foam cells in her bone marrow, liver, tongue, tonsils, glottis, and in normal-appearing peritonsillar mucosa. Lipid analysis of a liver biopsy specimen showed a small increase in phospholipids, a twofold increase in sphingomyelin, a fivefold increase in cholesterol, and a marked (25-fold) increase in bis(monoacylglycerol) phosphate. Lysosomal acid hydrolase activities in cultured skin fibroblasts were nondiagnostic. Biochemical and immunocytochemical studies of cultured fibroblasts demonstrated lysosomal accumulation of unesterified LDL-derived cholesterol as well as delayed induction of homeostatic responses to endogenous cholesterol consistent with a diagnosis of NPC. Based upon these observations, we speculate that this patient could have a new phenotypic expression of NPC or represents a new cholesterol lipidosis biochemically resembling NPC. The chance occurrence of two separate lipid disorders seems less likely.

Understanding the pathway for amyloid percursor protein (APP) catabolism has become an important line of investigation. APP is a ubiquitous membrane bound protein that is rapidly cleaved at the membrane, yielding a secreted protein identical to protease nexin II and an internalized 11.5 kDa 100 residue C terminal derivative (CTD). The levels of CTDs in a variety of cell lines have been examined and were found to differ. Cell types associated with the pathology of Alzheimer's disease (AD), such as olfactory neuroblasts (ON) and cortical vascular endothelial cells, have higher levels of CTDs than lymphoblasts and melanoma cells. The mechanism of CTD catabolism appears to involve the lysosome because blockade of lysosomal but not endosomal or mitochondrial function results in increased levels of CTDs. Under these conditions, production of larger, amyloidogenic CTDs is also seen. In cells possessing higher levels of CTDs we find that the mechanism for production of amyloidogenic CTDs may involve the internalization of intact full-length APP. Thus, inhibition of the lysosomal system appears capable of generating amyloidogenic peptides. The amount of amyloidogenic peptides appears to vary among cell lines. Such variation may shed light on why amyloid accumulates around specific cell types such as vascular endothelial cells, neurons, and glia. Finally, disfunction of the lysosomal system may play a role in the pathogenesis of Alzheimer's disease.

Purpose: To determine the clinical and radiographic characteristics of sinusitis in patients with human immunodeficiency virus type 1 (HIV-1) infection., Patients and Methods: A retrospective study was performed that identified all HIV-1-infected patients with sinus radiographs, sinus computed tomograms, or magnetic resonance imaging of the head between 1982 and 1989 (n = 145). Medical record review detailed the clinical course and laboratory parameters in all patients., Results: Eighty-nine patients had radiographic evidence of sinusitis; 75 patients had adequate clinical data and comprise the study group. Acute sinusitis was seen in 10 patients (13%), while all 75 patients had mucosal thickening indicative of chronic sinusitis. Fifty patients (67%) were symptomatic with fever, nasal congestion or discharge, and headache being the most common symptoms; nineteen patients (25%) were asymptomatic when their radiographs showed active disease. The mean CD4 count for the group was 276 cells/mm3; 32 (43%) had CD4 counts less than or equal to 100 cells/mm3. Twenty-three patients (31%) received antibiotics orally, parenterally, or both., Conclusions: Sinusitis appears to occur frequently in HIV-infected patients, is often asymptomatic, may be recurrent or refractory, and may be associated with declining immunocompetence in HIV-infected patients.

Objective: To prospectively study the clinical features, pathophysiology, treatment and prognosis of Wegener granulomatosis., Design: Of the 180 patients with Wegener granulomatosis referred to the National Institute of Allergy and Infectious Diseases during the past 24 years, 158 have been followed for 6 months to 24 years (a total of 1229 patient-years)., Measurements: Characteristics of clinical presentation, surgical pathology, course of illness, laboratory and radiographic findings, and the results of medical and surgical treatment have been recorded in a computer-based information retrieval system., Setting: The Warren Magnuson Clinical Center of the National Institutes of Health., Main Results: Men and women were equally represented; 97% of patients were white, and 85% were more than 19 years of age. The mean period of follow-up was 8 years. One hundred and thirty-three patients (84%) received "standard" therapy with daily low-dose cyclophosphamide and glucocorticoids. Eight (5.0%) received only low-dose cyclophosphamide. Six (4.0%) never received cyclophosphamide and were treated with other cytotoxic agents and glucocorticoids. Ten patients (6.0%) were treated with only glucocorticoids. Ninety-one percent of patients experienced marked improvement, and 75% achieved complete remission. Fifty percent of remissions were associated with one or more relapses. Of 99 patients followed for greater than 5 years, 44% had remissions of greater than 5 years duration. Thirteen percent of patients died of Wegener granulomatosis, treatment-related causes, or both. Almost all patients had serious morbidity from irreversible features of their disease (86%) or side effects of treatment (42%)., Conclusions: The course of Wegener granulomatosis has been dramatically improved by daily treatment with cyclophosphamide and glucocorticoids. Nonetheless, disease- and treatment-related morbidity is often profound. Alternative forms of therapy have not yet achieved the high rates of remission induction and successful maintenance that have been reported with daily cyclophosphamide treatment. Despite continued therapeutic success with cyclophosphamide, our long-term follow-up of patients with Wegener granulomatosis has led to increasing concerns about toxicity resulting from prolonged cyclophosphamide therapy and has encouraged investigation of other therapeutic regimens.

Based upon the radiation sensitization properties of the halogenated pyrimidines, 5-iododeoxyuridine (IdUrd) and 5-bromodeoxyuridine, long term i.v. infusions of halogenated pyrimidines in conjunction with fractionated radiation therapy have been evaluated in the treatment of a variety of human malignancies. While clinical studies have attempted to measure the halogenated pyrimidine incorporation, few have successfully related tumor response to the incorporation of IdUrd by the tumor. The present study reports the continuous IdUrd labeling index (number of cells labeled) and the IdUrd corrected replacement (percentage of thymidine replacement in the labeled cells of the population) from the tumors of 17 patients who received continuous infusions of IdUrd (1000 mg/m2/24 h). The tumors treated included four high grade gliomas, five head and neck tumors, four high grade sarcomas, and five other tumors of varying types. Less than 25% of the cells in three of four gliomas incorporated IdUrd after 5-7-day IdUrd infusion time. Corrected replacement for the gliomas ranged from 0 to 4%. In contrast, 63-85% of the cells in the head and neck biopsies were labeled with IdUrd after 3-7-day IdUrd infusions suggesting that these large tumors (3-12 cm diameter) have a high fraction of dividing cells. Corrected replacements values for the head and neck tumor patients ranged from 2.9 to 26.3%. The high grade sarcomas also demonstrated a high percentage of IdUrd labeled cells (57-79%) with three patients having corrected replacements of 7.5-14.2%. The continuous labeling and thymidine replacement data for four patients from whom serial biopsies were taken during IdUrd infusion demonstrated both an increasing IdUrd replacement and continuous labeling index with an increasing duration of IdUrd infusion. The clinical response of both the high grade glioma and head and neck tumor patients indicate that the IdUrd replacement and labeling data may provide some important predictive information with regard to the successful use of the halogenated pyrimidines in clinical radiation trials.

The majority of patients with classic Wegener's granulomatosis present with symptoms of head and neck disease; accordingly, accurate interpretation of biopsy specimens from these sites is essential. This report details the histologic findings in 126 head and neck biopsy specimens from 70 patients (36 male and 34 female). Tissues were obtained from the following sites: 60 nasal, 27 paranasal sinuses, 17 laryngeal, five periorbital, five oral, four middle ear, three mastoid, two external ear, and three salivary gland. Vasculitis, necrosis, and granulomatous inflammation together were seen in only 16% of all head and neck biopsy specimens. Both vasculitis and granulomatous inflammation were seen in 21% and vasculitis and necrosis in 23% of the biopsy specimens reviewed. We discuss the problems in differential diagnosis, particularly the importance of excluding granulomatous infectious processes, which can imitate the histopathologic features of Wegener's granulomatosis. Based on this study, we propose criteria for the diagnosis of Wegener's granulomatosis based on biopsy specimens from the head and neck region.

We performed a retrospective analysis of 50 patients with acute frontal sinusitis who came to the Albert Einstein College of Medicine affiliated hospitals between 1981 and 1984. Cases were analyzed for age and sex in an attempt to determine the sex predilection for this disease in various age groups. Of the 50 patients studied, 38 (76%) were male and 12 (24%) were female. When subdivided into adult (older than 21 years of age) and adolescent (11 to 21 years of age) subgroups, a similar male predominance was noted. Among adults (28 patients), 21 (75%) were male and 7 (25%) were female. Among adolescents (22 patients), 17 (77%) were male and 5 (23%) were female. Of the 50 patients studied, 3 developed intracranial complications. All of these latter patients (all males) were in the adolescent group. Our findings indicate that male adolescents may be a high risk subgroup for developing intracranial complications secondary to their sinus infections.

We report the clinical, light-microscopic, and ultrastructural features of a case of multifocal verruciform xanthoma in the upper aerodigestive tract of a child with a systemic lipid disorder. Lipid storage cells were found in liver, bone marrow, and as a component of verruciform xanthomas. To our knowledge this represents the first case of verruciform xanthoma reported in (a) a child, (b) as a multifocal lesion in the upper aerodigestive tract, (c) associated with a systemic lipid disorder, and (d) with ultrastructural evidence of lipid accumulation within endothelial cells. Although this patient presented with lesions involving the tongue and larnyx, subsequently lesions were found in the bone marrow and liver. Two months later more lesions were discovered on the epiglottis, posteior tongue, right glottis, and in grossly normal peritonsillar mucosa. Six months later a new oral lesion developed. Based upon these observations, we speculate that the pathogenesis of verruciform xanthoma involves accumulation of excess lipid in subepithelial sites which is scavenged by macrophages. Lipid-laden macrophages release epithelial growth factors that lead to epithelial hyperplasia. Depending on the degree of epithelial hyperplasia, the gross appearance of verruciform xanthomas may be flat, sessile, papillary, or verrucous.