Asunto(s)
Enfermedades de los Labios/patología , Labio/cirugía , Procedimientos Quirúrgicos Orales/efectos adversos , Sialometaplasia Necrotizante/patología , Adulto , Diagnóstico Diferencial , Humanos , Enfermedades de los Labios/etiología , Enfermedades de los Labios/cirugía , Neoplasias de los Labios/diagnóstico , Masculino , Mucocele/cirugía , Sialometaplasia Necrotizante/etiología , Sialometaplasia Necrotizante/cirugíaRESUMEN
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.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Fraccionamiento de la Dosis de Radiación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Idoxuridina/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Adulto , Anciano , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Dosis de Radiación , Inducción de RemisiónAsunto(s)
Mesotelioma/secundario , Glándula Parótida/patología , Neoplasias de la Parótida/secundario , Neoplasias Pleurales/patología , Biomarcadores de Tumor/análisis , Biopsia con Aguja , Carcinoma/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Mesotelioma/química , Mesotelioma/diagnóstico , Mesotelioma/patología , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Neoplasias de la Parótida/química , Neoplasias de la Parótida/diagnóstico , Neoplasias de la Parótida/patologíaRESUMEN
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.
Asunto(s)
Neoplasias del Oído/complicaciones , Saco Endolinfático , Trastornos de la Audición/complicaciones , Ligasas , Proteínas Supresoras de Tumor , Ubiquitina-Proteína Ligasas , Enfermedad de von Hippel-Lindau/complicaciones , Edad de Inicio , Audiometría , Encéfalo/patología , Fosa Craneal Posterior/diagnóstico por imagen , Fosa Craneal Posterior/patología , Neoplasias del Oído/diagnóstico , Saco Endolinfático/diagnóstico por imagen , Saco Endolinfático/patología , Genes Supresores de Tumor , Pérdida Auditiva/complicaciones , Humanos , Imagen por Resonancia Magnética , Mutación , Hueso Petroso/diagnóstico por imagen , Hueso Petroso/patología , Proteínas/genética , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
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.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/farmacología , Interleucina-1/farmacología , Interleucina-6/farmacología , Factores de Crecimiento Nervioso/farmacología , Vías Olfatorias/citología , Tirosina/metabolismo , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos B/análisis , Biomarcadores , Antígenos CD13/análisis , Antígenos CD40/análisis , Diferenciación Celular/efectos de los fármacos , Proteínas del Citoesqueleto/efectos de los fármacos , Proteínas del Citoesqueleto/metabolismo , Epitelio/química , Epitelio/efectos de los fármacos , Epitelio/enzimología , Proteínas del Ojo/análisis , Citometría de Flujo , Proteína GAP-43 , Proteínas de Unión al GTP/análisis , Humanos , Inmunohistoquímica , Proteínas de Filamentos Intermediarios/análisis , Glicoproteínas de Membrana/análisis , Proteínas Asociadas a Microtúbulos/análisis , Neprilisina/análisis , Proteínas del Tejido Nervioso/análisis , Moléculas de Adhesión de Célula Nerviosa/análisis , Proteínas de Neurofilamentos/análisis , Neuropéptidos/análisis , Mucosa Olfatoria , Nervio Olfatorio , Vías Olfatorias/enzimología , Neuronas Receptoras Olfatorias , Periferinas , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Receptores de Transferrina , Transducción de Señal/fisiología , Tirosina/efectos de los fármacos , Vimentina/análisisRESUMEN
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.
Asunto(s)
Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/cirugía , Laringoestenosis/etiología , Laringoestenosis/cirugía , Adulto , Dilatación , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Intubación Intratraqueal , Laringoestenosis/tratamiento farmacológico , Estudios Retrospectivos , TraqueostomíaRESUMEN
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.
Asunto(s)
Infecciones por VIH/complicaciones , Sinusitis/metabolismo , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/virología , Antígenos CD/inmunología , Membrana Basal/metabolismo , Recuento de Células , Células Cultivadas , VIH-1/inmunología , VIH-1/metabolismo , Humanos , Inmunohistoquímica , Mucosa Nasal , Serotipificación , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
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.
Asunto(s)
Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Idoxuridina/uso terapéutico , Adulto , Anciano , Cromatografía Líquida de Alta Presión , Terapia Combinada , Femenino , Citometría de Flujo , Neoplasias de Cabeza y Cuello/patología , Humanos , Idoxuridina/administración & dosificación , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Proyectos Piloto , Radioterapia/métodos , Factores de TiempoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Nervio Olfatorio/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/análisis , Electroforesis en Gel Bidimensional , Femenino , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Neuronas/metabolismo , Nervio Olfatorio/citologíaRESUMEN
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.
Asunto(s)
Adenosina Monofosfato/fisiología , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/metabolismo , Mucosa Olfatoria/inervación , Nervio Olfatorio/patología , Fragmentos de Péptidos/metabolismo , Adolescente , Adulto , Anciano , Biopsia , Línea Celular , Células Cultivadas , Epitelio/patología , Femenino , Sustancias de Crecimiento/fisiología , Humanos , Isoproterenol/farmacología , Masculino , Persona de Mediana Edad , Mucosa Nasal/inervación , Mucosa Nasal/patología , Neuronas/patología , Teofilina/farmacologíaRESUMEN
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.
Asunto(s)
Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Fotorradiación con Hematoporfirina , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Humanos , Idoxuridina/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Hidrolasas de Éster Carboxílico/análisis , Otitis Media con Derrame/enzimología , Adolescente , Sangre , Hidrolasas de Éster Carboxílico/metabolismo , Niño , Preescolar , Enfermedad Crónica , Drenaje , Exudados y Transudados/enzimología , Pérdida Auditiva Conductiva/enzimología , Pérdida Auditiva Conductiva/cirugía , Humanos , Lactante , Ventilación del Oído Medio , Otitis Media con Derrame/patología , Estudios Prospectivos , RecurrenciaRESUMEN
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.
Asunto(s)
Granulomatosis con Poliangitis/fisiopatología , Adolescente , Adulto , Factores de Edad , Niño , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Oftalmopatías/fisiopatología , Femenino , Estudios de Seguimiento , Glomerulonefritis/fisiopatología , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Laringoestenosis/fisiopatología , Enfermedades Pulmonares/fisiopatología , Masculino , Enfermedades Nasales/fisiopatología , Infecciones Oportunistas , Prednisona/efectos adversos , Prednisona/uso terapéutico , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Granulomatosis con Poliangitis/cirugía , Laringoestenosis/cirugía , Estenosis Traqueal/cirugía , Adolescente , Adulto , Cartílago/trasplante , Niño , Terapia Combinada , Dilatación , Femenino , Glotis , Glucocorticoides/uso terapéutico , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Laringoestenosis/tratamiento farmacológico , Laringe/cirugía , Terapia por Láser , Masculino , Persona de Mediana Edad , Reoperación , Colgajos Quirúrgicos/métodos , Tráquea/cirugía , Estenosis Traqueal/tratamiento farmacológico , TraqueostomíaRESUMEN
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.
Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Variación Antigénica , Neuronas/fisiología , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/inmunología , Astrocitos , Secuencia de Bases , Línea Celular , Células Cultivadas , Epitelio/fisiología , Exones , Humanos , Immunoblotting , Riñón , Datos de Secuencia Molecular , Vías Olfatorias/fisiología , Oligodesoxirribonucleótidos , Reacción en Cadena de la Polimerasa/métodos , TransfecciónRESUMEN
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.
Asunto(s)
Hiperlipidemias , Enfermedades de Niemann-Pick , Xantogranuloma Juvenil , Biopsia , Preescolar , Colesterol/metabolismo , Femenino , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Enfermedades de Niemann-Pick/metabolismo , Enfermedades de Niemann-Pick/patología , Fenotipo , Xantogranuloma Juvenil/metabolismo , Xantogranuloma Juvenil/patologíaRESUMEN
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.
Asunto(s)
Precursor de Proteína beta-Amiloide/biosíntesis , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Antimetabolitos/farmacología , Línea Celular , Cloroquina/metabolismo , Humanos , Immunoblotting , Inmunohistoquímica , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Monensina/farmacología , Neuronas/efectos de los fármacos , Neuronas/ultraestructuraRESUMEN
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.
Asunto(s)
Infecciones por VIH/complicaciones , VIH-1 , Sinusitis/diagnóstico , Adulto , Linfocitos T CD4-Positivos , Femenino , Humanos , Recuento de Leucocitos , Imagen por Resonancia Magnética , Masculino , Radiografía , Estudios Retrospectivos , Sinusitis/sangre , Sinusitis/diagnóstico por imagen , Sinusitis/microbiologíaRESUMEN
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.