RESUMEN
Goodpasture's syndrome is a rare vasculitis associated with anti-glomerular basement membrane (anti-GBM) autoantibodies that target type IV collagen found in the basement membranes of glomeruli and alveoli. We present a case of a 79-year-old man with seronegative Goodpasture's syndrome with predominant respiratory symptoms and mild acute kidney injury that initially improved. Final diagnosis was made by immunofluorescent staining on open lung biopsy which also revealed concomitant organising pneumonia. The patient underwent treatment with corticosteroids, cyclophosphamide, haemodialysis and plasmapheresis. This was an atypical presentation wherein the patient only exhibited pulmonary symptoms early in the course of illness in the setting of negative anti-GBM antibody serum testing, which made diagnosis challenging. With this case, we emphasise that clinicians should have a high suspicion for Goodpasture's syndrome in the setting of unexplained severe pulmonary or renal disease despite negative anti-GBM antibody testing.
Asunto(s)
Lesión Renal Aguda/diagnóstico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/diagnóstico , Neumonía/diagnóstico , Lesión Renal Aguda/terapia , Anciano , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Antiinfecciosos/uso terapéutico , Biomarcadores/análisis , Broncoscopía , Diagnóstico Diferencial , Resultado Fatal , Humanos , Intubación Intratraqueal , Masculino , Plasmaféresis , Neumonía/terapia , Diálisis Renal , Esteroides/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Missense mutations in human cationic trypsinogen PRSS1 are frequently detected in patients with hereditary pancreatitis, a rare genetic disease of the pancreas characterized by autodigestive necrosis, chronic inflammation, and fibrosis. To examine the link between PRSS1 mutations and the initiation and progression of hereditary pancreatitis, we have sought to generate a transgenic mouse that carries a missense mutation in the PRSS1 that is most frequently observed in patients. METHODS: A transgenic mouse was generated in which the expression of the mouse PRSS1 mutant R122H (R122H_mPRSS1) is targeted to pancreatic acinar cells by fusion to the elastase promoter. The expression of the mutant trypsinogen was assessed by immunohistochemical staining and real-time reverse transcription polymerase chain reaction analysis. The relationship between transgene expression and inflammation was analyzed by morphologic assessment of H&E-stained tissue sections, responsiveness to cerulein-induced pancreatitis, and immunohistochemical identification of cellular and biochemical components of the inflammatory response. RESULTS: Pancreata from transgenic mice display early-onset acinar cell injury and inflammatory cell infiltration. With progressing age, the transgenic mice develop pancreatic fibrosis and display acinar cell dedifferentiation. Moreover, the expression of R122H_mPRSS1 transgene is associated with enhanced response to cerulein-induced pancreatitis. Finally, cell-specific activation of the inflammation-associated signaling pathways, c-jun-N-terminal kinase and extracellular signal-regulated kinase, was observed in response to expression of R122H_mPRSS1. CONCLUSIONS: These results underscore the importance of PRSS1 mutations as pathogenic mediators of hereditary pancreatitis and indicate that persistent pancreatic injury might be causally linked to chronic pancreatitis.
Asunto(s)
Regulación de la Expresión Génica , Pancreatitis Crónica/genética , Pancreatitis Crónica/patología , Tripsinógeno/genética , Animales , Ceruletida/farmacología , ADN/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación Missense/genética , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Pancreatitis Crónica/metabolismo , Fenotipo , Tripsinógeno/metabolismoRESUMEN
Pancreatic cancer is a challenging disease for patients, doctors and researchers who for decades have searched for a cure for this deadly malignancy. Although existing mouse models of pancreatic cancer have shed light on the mechanistic basis of the neoplastic conversion of the pancreas, their impact in terms of offering new diagnostics and therapeutic modalities remains limited. Chronic pancreatitis is an inflammatory disease of the pancreas that is associated with a gradual damage of the organ and an increased risk of developing neoplastic lesions. In this review, we propose that detailed studies of chronic inflammatory processes in the pancreas will provide insights into the evolution of pancreatic cancer. This information may prove useful in the design of effective therapeutic strategies to battle the disease.
Asunto(s)
Adenocarcinoma/patología , Neoplasias Pancreáticas/patología , Pancreatitis/patología , Animales , Diabetes Mellitus/patología , Modelos Animales de Enfermedad , Humanos , Inflamación , Ratones , MutaciónRESUMEN
Lyme carditis is becoming a more frequent complication of Lyme disease, primarily due to the increasing incidence of this disease in the United States. Cardiovascular manifestations of Lyme disease often occur within 21 days of exposure and include fluctuating degrees of atrioventricular (AV) block, acute myopericarditis or mild left ventricular dysfunction and rarely cardiomegaly or fatal pericarditis. AV block can vary from first-, second-, third-degree heart block, to junctional rhythm and asystolic pauses. Patients with suspected or known Lyme disease presenting with cardiac symptoms, or patients in an endemic area presenting with cardiac symptoms with no other cardiac risk factors should have a screening electrocardiogram along with Lyme titers. We present a case of third-degree AV block due to Lyme carditis, illustrating one of the cardiac complications of Lyme disease. This disease is usually self-limiting when treated appropriately with antibiotics, and does not require permanent cardiac pacing.
Asunto(s)
Bloqueo Cardíaco/etiología , Enfermedad de Lyme/complicaciones , Miocarditis/complicaciones , Ceftriaxona/administración & dosificación , Quimioterapia Combinada , Electrocardiografía , Femenino , Estudios de Seguimiento , Bloqueo Cardíaco/diagnóstico , Bloqueo Cardíaco/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Enfermedad de Lyme/diagnóstico , Persona de Mediana Edad , Miocarditis/diagnóstico , Prednisona/administración & dosificación , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Oral cavity mucositis is a major toxicity of radiation therapy for head and neck cancer. In the present mouse model studies, we evaluated intraoral administration of SOD2-PL complexes 24 h before single-fraction 30-Gy irradiation for the prevention of oral cavity mucositis. Expression of the human SOD2 transgene in the oral cavity of C3H/HeNsd mice was demonstrated by nested reverse transcriptase polymerase chain reaction (RT-PCR). Mice treated intraorally with bacterial beta-galactosidase gene-plasmid/liposome (LacZ-PL) or hemagglutinin (HA)-manganese superoxide dismutase-plasmid/liposome (HA-SOD2-PL) demonstrated LacZ or HA-SOD2 expression, respectively, 24 h after injection. In a second strain of mouse, SOD2-PL-treated female athymic nude mice demonstrated significantly decreased ulceration at day 5 after 30 Gy, compared to LacZ-PL-injected, irradiated mice or irradiated controls. No further reduction in radiation-induced ulceration was detected in mice treated with both SOD2-PL and 10 mg/kg of amifostine (WR-2721) 30 min before 30 Gy compared to SOD2-PL alone. No significant protection of orthotopically transplanted murine squamous cell carcinoma (SCC-VII) tumors was detected in mice that received SOD2-PL treatment before 18 Gy. Thus overexpression of human SOD2 in the oral cavity mucosa can prevent radiation-induced mucositis with no detectable compromise in the therapeutic response of orthotopically transplanted tumors.
Asunto(s)
Vectores Genéticos , Liposomas/metabolismo , Mucosa Bucal/patología , Mucosa Bucal/efectos de la radiación , Plásmidos/metabolismo , Superóxido Dismutasa/genética , Transgenes , Animales , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Inmunohistoquímica , Operón Lac , Ratones , Ratones Desnudos , Membrana Mucosa/patología , Trasplante de Neoplasias , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Lengua/patología , Lengua/efectos de la radiación , beta-Galactosidasa/metabolismoRESUMEN
Pulmonary toxicity is a major complication of total body irradiation used in preparation of patients for bone marrow transplantation. The mechanism of the late pulmonary damage manifested by fibrosis is unknown. In C57BL/6NHsd mice, manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) intratracheal injection 24 hours prior to 20 Gy single-fraction irradiation to both lungs significantly reduced late irradiation damage. Single intratracheal injections of MnSOD-PL, at concentrations as low as 250 microg of plasmid DNA, in a constant volume of 78 microL of liposomes, reduced late damage. To determine whether a slowly proliferating population of cells in the lung was responsible for initiation of fibrosis and was altered by MnSOD-PL therapy, 20 Gy total lung-irradiated mice were examined at serial time points for bromodeoxyuridine (BrdU) uptake in sites of cell division. There was low-level, but nonsignificant, increased cell proliferation detected at 80 days, with a significant increase at 100 days, 120 days, and at the time of death. Immunohistochemical assay for up-regulation of adhesion molecules associated with recruitment, transendothelial migration, and proliferation of bronchoalveolar macrophages revealed significant up-regulation of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) at 100 days with further increases up to the time of death. Increases were first detected in endothelin-positive endothelial cells. MnSOD-PL administration prior to irradiation decreased both BrdU incorporation and delayed expression of VCAM-1 and ICAM-1. The data indicate that the appearance of late irradiation-induced pulmonary fibrosis is associated with the up-regulation of adhesion molecules and suggest that potential targets for intervention may focus on the pulmonary vascular endothelium.