RESUMEN
BACKGROUND: Keloid lesions are characterized by mesenchymal cell proliferation and excessive extracellular matrix deposition. Previous microarray analyses have been performed to investigate the mechanism of keloid development. However, the molecular pathology that contributes to keloid development remains obscure. AIM: To explore the underlying essential molecules of keloids using microarrays. METHODS: We performed microarray analyses of keloid and nonlesional skin tissues both in vivo and in vitro. Gene expression levels were compared between tissues and cells. Quantitative reverse transcription (qRT)-PCR and immunohistochemical staining were used to determine the expression levels of molecules of interest in keloid tissues. RESULTS: Several common molecules were upregulated in both keloid tissues and keloid-lesional fibroblasts. PTPRD and NTM were upregulated both in vivo and in vitro. The genes MDFI and ITGA4 were located at the centre of the gene coexpression network analysis using keloid tissues. qRT-PCR revealed significant expression levels of PTPRD and MDFI in keloid tissues. Immunopathological staining revealed that MDFI-positive cells, which have fibroblast characteristics, were located in the keloid-associated lymphoid tissue (KALT) portion of the keloid tissue. CONCLUSION: Our gene expression profiles of keloids could distinguish the difference between lesional tissue and cultured lesional fibroblasts, and MDFI was found to be commonly expressed in both tissues and cells. Thus, MDFI-positive cells, which were located in the KALT, may play an important role in keloid pathogenesis and thus might be useful for in vitro keloid studies.
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Perfilación de la Expresión Génica , Expresión Génica , Queloide/genética , Factores Reguladores Miogénicos/genética , Diagnóstico Diferencial , Fibroblastos/metabolismo , Humanos , Inmunohistoquímica , Queloide/metabolismo , Análisis por Micromatrices , Factores Reguladores Miogénicos/metabolismo , ARN/análisis , ARN Mensajero/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in Japan. Treatment with inhibitors of the vascular endothelial growth factor (VEGF) signalling pathway has proven benefit in metastatic CRC. Cediranib is an oral highly potent VEGF signalling inhibitor that inhibits all three VEGF receptors. PATIENTS AND METHODS: In this phase II, double-blind, placebo-controlled study, 172 patients with metastatic CRC were randomised to receive once-daily cediranib (20 or 30 mg) or placebo, each combined with modified FOLFOX6 (mFOLFOX6). The primary objective was comparison of progression-free survival (PFS). RESULTS: The comparison of cediranib 20 mg versus placebo met the primary objective of PFS prolongation [hazard ratio = 0.70 (95% confidence interval 0.44-1.11), P = 0.167], which met the protocol-defined criterion of P < 0.2. Median PFS was 10.2 versus 8.3 months, respectively. The PFS comparison for cediranib 30 mg versus placebo did not meet the criterion. The most common adverse events (AEs) in the cediranib-containing groups were diarrhoea and hypertension. CONCLUSIONS: Cediranib 20 mg plus mFOLFOX6 met the predefined criteria in terms of improved PFS compared with placebo plus mFOLFOX6. Cediranib 20 mg was generally well tolerated and the AE profile was consistent with previous studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Carcinoma/secundario , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/sangre , Carcinoma/mortalidad , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Humanos , Japón , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Quinazolinas/administración & dosificación , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
We report a case of segmental uniparental maternal hetero- and isodisomy involving the whole of chromosome 6 (mat-hUPD6 and mat-iUPD6) and a cullin 7 (CUL7) gene mutation in a Japanese patient with 3M syndrome. 3M syndrome is a rare autosomal recessive disorder characterized by severe pre- and postnatal growth retardation that was recently reported to involve mutations in the CUL7 or obscurin-like 1 (OBSL1) genes. We encountered a patient with severe growth retardation, an inverted triangular gloomy face, an inverted triangle-shaped head, slender long bones, inguinal hernia, hydrocele testis, mild ventricular enlargement, and mild mental retardation. Sequence analysis of the CUL7 gene of the patient revealed a homozygous missense mutation, c.2975G>C. Genotype analysis using a single nucleotide polymorphism array revealed two mat-hUPD and two mat-iUPD regions involving the whole of chromosome 6 and encompassing CUL7. 3M syndrome caused by complete paternal iUPD of chromosome 6 involving a CUL7 mutation has been reported, but there have been no reports describing 3M syndrome with maternal UPD of chromosome 6. Our results represent a combination of iUPDs and hUPDs from maternal chromosome 6 involving a CUL7 mutation causing 3M syndrome.
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Cromosomas Humanos Par 6/genética , Proteínas Cullin/genética , Enanismo/genética , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Disomía Uniparental/genética , Preescolar , Femenino , Humanos , Masculino , Mutación Missense , Columna Vertebral/anomalíasRESUMEN
Ablation of expanded polytetrafluoroethylene without disruption of the fine porous structure is demonstrated using an intense femtosecond-pulse laser. As a result of laser-matter interactions near ablation threshold fluence, high-energy ions are emitted, which cannot be produced by thermal dissociation of the molecules. The ion energy is produced by Coulomb explosion of the elements of (-CF(2)-CF(2)-)(n) and the energy spectra of the ions show contributions from the Coulomb explosions of the ions rather than those of thermal expansion to generate high-energy ions. The dependence of ion energy on the laser fluence of a 180-fs pulse, compared with that of a 400-ps pulse, also suggests that the high-energy ions are accelerated by Coulomb explosion.
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Rayos Láser , Óptica y Fotónica , Politetrafluoroetileno/química , Carbono/química , Diseño de Equipo , Iones , Espectrometría de Masas/métodos , Microscopía Electrónica de Rastreo/métodos , Modelos Estadísticos , Distribución Normal , Física/métodos , Polímeros/química , PorosidadRESUMEN
BACKGROUND/AIMS: This study assessed the efficacy and toxicity of the FOLFOX4 (SWIFT1) and mFOLFOX6 (SWIFT2) regimens in Japanese patients with metastatic colorectal cancer (mCRC). METHODOLOGY: Patients with mCRC were required to have ECOG performance status of 0 to 1, and to have adequate organ function. Two multicenter Phase II studies (SWIFT1/SWIFT2) were conducted in chemotherapy naive patients with mCRC. RESULTS: 112 patients were enrolled in these studies (SWIFT1: 54 patients / SWIFT2: 58 patients). The disease sites for each study were the colon in 27 patients and 28 patients, and the rectum in 27 patients and 30 patients, respectively. All patients received a median of 8 courses. After a median follow-up period of 35 months, 54 patients and 58 patients were evaluable in the respective studies, and the overall response rate was 50.0% (CR:31 PR:53). The response rate according to the sites of metastasis were as follows: liver, 54.1% (46/85); lung, 17.4% (4/23); and lymph node, 23.3% (7/30). Grade 3/4 neutropenia occurred in 14 patients (12.5%), while Grade 3/4 non-hematological toxicities were observed in 16 patients (31.0%) and Grade 3 neurotoxicity was observed in 6patients (5.4%) and 5 patients (4.5%), respectively. CONCLUSIONS: FOLFOX4 (SWIFT1) and mFOLFOX6 (SWIFT2) regimens complying with the international standard dosage and schedule can also be administered safely and effectively in Japan.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/uso terapéuticoRESUMEN
BACKGROUND: Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. PATIENTS AND METHODS: Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1-54.9) and 9.1 months (95% CI, 8.6-11.1) in group A, compared with 47.4% (80% CI, 39.1-55.8) and 9.3 months (95% CI, 6.0-13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). CONCLUSION: Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. TRIAL REGISTRATION NUMBER: NCT02337946.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Panitumumab/administración & dosificación , Panitumumab/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Resultado del TratamientoRESUMEN
BACKGROUND: The role of gastrectomy in the treatment of advanced gastric cancer patients with non-curative factors remains controversial. We investigated prognostic factors and evaluated the role of gastrectomy in such patients. PATIENTS AND METHODS: Eighty-eight advanced gastric cancer patients with non-curative factors were prospectively studied. The patients were categorized into the following two groups: Group A: 52 patients who underwent gastrectomy and subsequently received chemotherapy, Group B: 36 patients who received chemotherapy alone. RESULTS: The median survival times of group A and B patients were 351 and 182 days, respectively (p=0.008). Multivariate analysis showed that gastrectomy was the only positive independent prognostic factor, with no effect on the results of chemotherapy. There was no significant difference in the duration of hospital stay between patients of the two groups, while significantly longer maintenance of oral intake was observed for group A. CONCLUSION: In advanced gastric cancer patients with non-curative factors, gastrectomy was beneficial for survival with longer maintenance of oral intake.
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Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Terapia Combinada , Femenino , Gastrectomía , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Calidad de Vida , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
The clinical significance of a proper eye drop application technique was evaluated in Japanese glaucoma patients. Patients diagnosed with primary open-angle glaucoma having intraocular pressure (IOP) greater than 21 mmHg were treated with eye drops at home. In some patients, however, the topical treatment was ineffective. They returned to the hospital to receive surgical treatment. On admission, 56% of these patients had IOP greater than 21 mmHg. Patient instillation technique was evaluated based on the proximity of the eyedropper tip to the eyes, application position, eyelid closure, treatment (removal) of excess fluid, and nasolacrimal occlusion. In addition, pharmacists interviewed patients to determine the level of understanding of glaucoma, knowledge of prescribed drugs, home application technique, and sensation after application. Multivariate analysis revealed that the key factors influencing the control of IOP to less than 21 mmHg with topical medication were: application of drops in the center of the eye and removal of excessive fluid, in addition to gender and age. Proper topical application at home was dependent on the patient's understanding of the disease, knowledge of prescribed drugs, patient education on the use of drugs, the competence of the instructor, and knowledge of correct application technique. This study indicates that easily comprehensible patient education on the use of eye drops, the nature of glaucoma and the proper use of prescribed drugs is vital to improving the clinical efficacy of topical ophthalmic medication of glaucoma in adult patients.
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Glaucoma/tratamiento farmacológico , Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/uso terapéutico , Administración Tópica , Adulto , Anciano , Femenino , Glaucoma/diagnóstico , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Análisis Multivariante , Soluciones Oftálmicas/efectos adversos , FarmacéuticosRESUMEN
Activated CD4+ helper T cells have been demonstrated in asthmatic airways and postulated to play a central role in eliciting allergic inflammation; direct evidence of their involvement seems to be lacking. We hypothesized that CD4+ T cells have the potential to induce allergic responses to antigen challenge, and tested this hypothesis in a model of allergic bronchoconstriction, the Brown Norway rat, using the approach of adoptive transfer. Animals were actively sensitized to either ovalbumin (OVA) or BSA and were used as donors of T cells. W3/25(CD4)+ or OX8(CD8)+ T cells were isolated from the cervical lymph nodes of sensitized donors and transferred to naive BN rats. 2 d after adoptive transfer recipient rats were challenged by OVA inhalation, and changes in lung resistance (RL), bronchoalveolar lavage (BAL) cells, and serum levels of antigen-specific IgE were studied. After OVA challenge recipients of OVA-primed W3/25+ T cells exhibited sustained increases in RL throughout the entire 8-h observation period and had significant bronchoalveolar lavage eosinophilia, which was detected by immunocytochemistry using an antimajor basic protein mAb. Recipients of BSA-primed W3/25+ T cells or OVA-primed OX8+ T cells failed to respond to inhaled OVA. OVA-specific immunoglobulin E was undetectable by ELISA or skin testing in any of the recipient rats after adoptive transfer. In conclusion, antigen-induced airway bronchoconstriction and eosinophilia were successfully transferred by antigen-specific W3/25+ T cells in Brown Norway rats. These responses were dependent on antigen-primed W3/25+ T cells and appeared to be independent of IgE-mediated mast cell activation. This study provides clear evidence for T cell mediated immune mechanisms in allergic airway responses in this experimental model.
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Alérgenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Hipersensibilidad/inmunología , Inmunoterapia Adoptiva , Pulmón/inmunología , Sistema Respiratorio/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Linfocitos T CD8-positivos/inmunología , Eosinófilos/citología , Eosinófilos/inmunología , Inmunidad Celular , Inmunoglobulina E/análisis , Inflamación , Recuento de Leucocitos , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Transfusión de Linfocitos , Masculino , Ovalbúmina/inmunología , Ratas , Ratas Endogámicas BN , Albúmina Sérica Bovina/inmunología , Pruebas CutáneasRESUMEN
Bone morphogenetic proteins (BMPs) are pleiotropic growth and differentiation factors belonging to the transforming growth factor-beta (TGF-beta) superfamily. Signals of the TGF-beta-like ligands are propagated to the nucleus through specific interaction of transmembrane serine/threonine kinase receptors and Smad proteins. GCCGnCGC has been suggested as a consensus binding sequence for Drosophila Mad regulated by a BMP-like ligand, Decapentaplegic. Smad1 is one of the mammalian Smads activated by BMPs. Here we show that Smad1 binds to this motif upon BMP stimulation in the presence of the common Smad, Smad4. The binding affinity is likely to be relatively low, because Smad1 binds to three copies of the motif weakly, but more repeats of the motif significantly enhance the binding. Heterologous reporter genes (GCCG-Lux) with multiple repeats of the motif respond to BMP stimulation but not to TGF-beta or activin. Mutational analyses reveal several bases critical for the responsiveness. A natural BMP-responsive reporter, pTlx-Lux, is activated by BMP receptors in P19 cells but not in mink lung cells. In contrast, GCCG-Lux responds to BMP stimulation in both cells, suggesting that it is a universal reporter that directly detects Smad phosphorylation by BMP receptors.
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Proteínas Morfogenéticas Óseas/farmacología , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila , Elementos de Respuesta/genética , Transactivadores/metabolismo , Factores de Transcripción , Activación Transcripcional/efectos de los fármacos , Activinas , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Secuencia de Consenso/genética , ADN/genética , ADN/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Genes Reporteros/genética , Inhibinas/farmacología , Proteínas de Insectos/farmacología , Ratones , Mutación/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Secuencias Repetitivas de Ácidos Nucleicos/genética , Transducción de Señal/efectos de los fármacos , Proteínas Smad , Proteína Smad1 , Proteína Smad4 , Transactivadores/química , Transactivadores/genética , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.
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Adenocarcinoma/genética , Carcinoma de Células en Anillo de Sello/genética , Diferenciación Celular , Neoplasias Colorrectales/genética , Mutación/genética , Proteína Smad4/genética , Adenocarcinoma/patología , Carcinoma de Células en Anillo de Sello/patología , Neoplasias Colorrectales/patología , ADN de Neoplasias , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Proteína Smad4/metabolismoRESUMEN
A 59-year-old Japanese woman was referred to our hospital due to upper abdominal pain. At the age of 44, she was diagnosed with a congenital choledochal cyst, Todani's type Ic. She then underwent bypass operation with end-to-side choledochojejunostomy with Roux-en-Y technique as well as cholecystectomy. Magnetic resonance cholangiopancreatography revealed an 'oval' shaped cystic lesion with a maximal diameter of 25 mm, which had been 'spindle' shaped with a maximal diameter of 18 mm, 15 years ago. It also showed an anomalous pancreaticobiliary ductal union. In addition, a complete absence of the dorsal primordia of pancreas was revealed by magnetic resonance image and computed tomography scan. The patient underwent the surgical exploration for the resection of the 'oval' shaped cystic lesion. Haematoxylin and eosin staining of the thin section of the resected cyst showed a compact spindle cell pattern which was compatible with schwannoma, Antoni type A, which was confirmed by immunocytochemical technique. We present a very interesting case showing choledochal cyst, anomalous pancreaticobiliary ductal union, total agenesis of the dorsal pancreas and late-development of bile duct schwannoma in the remnant choledochal cyst.
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Neoplasias de los Conductos Biliares/patología , Quiste del Colédoco/complicaciones , Neurilemoma/patología , Páncreas/anomalías , Dolor Abdominal/etiología , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares/patología , Conductos Biliares/cirugía , Femenino , Humanos , Japón , Persona de Mediana Edad , Neurilemoma/complicaciones , Neurilemoma/cirugía , Resultado del TratamientoRESUMEN
PURPOSE: To report a case of subretinal neovascularization associated with retinochoroidal coloboma. METHODS AND RESULTS: A 44-year-old female presented with metamorphopsia in her right eye for 4 weeks. Funduscopic examination revealed bilateral inferior retinochoroidal coloboma. Fluorescein angiography disclosed foci of subretinal neovascularization at the margin between the colobomatous defect and the normal-appearing retina. Five month later, multiple small areas of subretinal hemorrhages were noted. The hemorrhage was gradually absorbed. Six years after initial presentation, subretinal hemorrhage did not recur and her right VA was 0.2. CONCLUSIONS: Ophthalmologists should be aware of this rare but important complication of retinochoroidal coloboma.
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Coroides/anomalías , Coloboma/complicaciones , Retina/anomalías , Neovascularización Retiniana/etiología , Adulto , Coroides/patología , Coloboma/diagnóstico , Femenino , Angiografía con Fluoresceína , Humanos , Retina/patología , Neovascularización Retiniana/diagnóstico , Trastornos de la Visión/etiología , Agudeza VisualRESUMEN
To understand corneal stromal wound healing, we investigated the effect of fibronectin (FN) on the phagocytic activity of rabbit corneal keratocytes. The phagocytic activity was measured under a dark-field microscope using polystyrene latex beads coated with either FN, bovine serum albumin, or both. The percentage of phagocytosing cells increased with incubation time. The phagocytic activity was significantly enhanced in a dose-dependent manner by coating beads with FN. Transmission electron microscopic observation demonstrated that latex beads were internalized into the cytoplasm and were surrounded by limiting membranes. These findings indicate that cultured keratocytes have phagocytic activity and that FN shows opsonic effects on the phagocytic activity, suggesting that FN in the injured corneal stroma may play a role in stromal wound repair by opsonic effects.
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Córnea/citología , Fibronectinas/farmacología , Fagocitosis/efectos de los fármacos , Animales , Recuento de Células , Células Cultivadas , Córnea/fisiología , Córnea/ultraestructura , Látex , Microscopía Electrónica , Microesferas , Conejos , Factores de TiempoRESUMEN
The nicotinamide N-oxide reductase activity of a variety of ocular tissues was investigated. The 9,000g supernatant of ciliary body, retinal pigment epithelium-choroid, iris, retina and cornea, but not lens, exhibited reductase activity under anaerobic conditions when supplemented with 2-hydroxypyrimidine, an electron donor of aldehyde oxidase. Among these tissues, the highest activity was observed with ciliary body. When the 9,000g supernatant of ciliary body was fractionated, the 2-hydroxypyrimidine-linked reductase activity was mainly associated with the cytosolic fraction and was markedly inhibited by menadione, an inhibitor of aldehyde oxidase. Similarly, in the presence of 2-hydroxypyrimidine, the cytosolic fraction of rabbit ciliary body exhibited nicotinamide N-oxide reductase activity which was susceptible to inhibition by menadione. These facts strongly suggest that aldehyde oxidase present in mammalian eyes is involved in the reduction of nicotinamide N-oxide to nicotinamide.
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Aldehído Oxidorreductasas/metabolismo , Ojo/enzimología , Aldehído Oxidasa , Animales , Bovinos , Fraccionamiento Químico , Cuerpo Ciliar/enzimología , Cuerpo Ciliar/metabolismo , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Oxidación-Reducción , ConejosRESUMEN
PURPOSE: To understand the cellular mechanism underlying the relaxation of ciliary muscle, relaxation induced by prostaglandins (PGs) and some other agents was characterized in the cat. METHODS: Tone of isolated ciliary muscle was measured by means of a force-displacement transducer. Adenylate cyclase activity was determined with membrane fraction of ciliary muscle by measuring the formation of cyclic adenosine monophosphate (cAMP). RESULTS: The addition of various PGs and isoproterenol relaxed the ciliary muscle that had been precontracted with 3 x 10(-6) M carbachol. The relaxation was dose dependent, with an EC50 of 2 x 10(-7) M for PGE2. The rank order of potency by which PGs induced relaxation (PGE2 = E1 > D2 > F2 alpha > I2) was identical with that reported for EP type prostaglandin receptor-mediated responses except for PGD2, which was more potent than expected. Agents that increased cellular cAMP, such as forskolin and IBMX, also relaxed the precontracted muscle. Nitric oxide donors, such as sodium nitroprusside and S-nitroso-N-acetyl-DL-penicillamine (SNAP), also caused dose-dependent relaxation. PGs and isoproterenol, but not nitroprusside, stimulated adenylate cyclase. The rank order of potency by which PGs stimulate adenylate cyclase was similar to that observed for muscle relaxation, suggesting that cAMP is the cellular second messenger for the PG-induced muscle relaxation and thus that PG receptors of EP2 and DP type are involved. CONCLUSIONS: Relaxation of cat ciliary muscle is mediated by two independent mechanisms: a cAMP-dependent one, which includes beta-adrenergic, EP2, and DP receptor-mediated responses, and a cAMP-independent one, which includes the nitric oxide-induced mechanism.
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Cuerpo Ciliar/fisiología , Relajación Muscular/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Agonistas Adrenérgicos beta/farmacología , Animales , Carbacol/farmacología , Gatos , Cuerpo Ciliar/efectos de los fármacos , AMP Cíclico/metabolismo , Contracción Muscular/efectos de los fármacos , Músculos/efectos de los fármacos , Músculos/fisiología , Óxido Nítrico/farmacología , Prostaglandinas/farmacologíaRESUMEN
Epidermal growth factor (EGF) stimulates corneal epithelial migration in vivo and in vitro. Antibody against fibronectin inhibits this effect in vitro, suggesting that a fibronectin-dependent mechanism in involved. To elucidate the action of EGF, we placed rabbit corneal epithelial cells, preincubated in the absence or presence of EGF (10 ng/ml), into wells coated with fibronectin. After 45 minutes of incubation, the numbers of cells attached to the wells were counted. Preincubation with EGF for 6 hr was not effective, but preincubation for 9 hr significantly increased the numbers of cells attached to the wells. These numbers were not increased further by additional preincubation. When concentrations of EGF were reduced, numbers of attached cells decreased proportionally, but remained significantly higher than the numbers obtained with cells not exposed to EGF. The EGF-stimulated attachment to the fibronectin matrix was inhibited in a dose-dependent fashion by antifibronectin IgG and by GRGDSP, a synthetic peptide that mimics the amino acid sequence of the cell-binding domain of fibronectin. The authors conclude that a fibronectin/fibronectin receptor system mediates EGF-induced stimulation of cellular attachment. These findings suggest that EGF may increase the expression of fibronectin receptors.
Asunto(s)
Córnea/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Fibronectinas/metabolismo , Receptores Inmunológicos/metabolismo , Secuencia de Aminoácidos , Animales , Adhesión Celular/efectos de los fármacos , Recuento de Células , Células Cultivadas , Córnea/citología , Córnea/efectos de los fármacos , Células Epiteliales , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Femenino , Fibronectinas/farmacología , Inmunoglobulina G , Datos de Secuencia Molecular , Oligopéptidos/farmacología , Conejos , Receptores de Antígenos/metabolismo , Receptores de Fibronectina , Cicatrización de Heridas/fisiologíaRESUMEN
Delivery of 2.1 microgram of cholera toxin, a specific, irreversible activator of adenylate cyclase, via the blood lowers IOP from 17.4 to 11.2 mm Hg in 81/2 hr. decreases net aqueous flow by about 50% in 8 hr, and doubles blood flow to the anterior uvea at 8 to 13 hr. Intravitreal injection of 0.26 microgram of cholera toxin lowered IOP from 15.0 to 9.6 mm Hg, but heat-inactivated toxin had no effect on IOP. The toxin activates adenylate cyclase from ciliary processes 2.2-fold and stimulates cyclic AMP production by ciliary processes 7.4 times. Absence of aqueous flare, normal protein concentrations in the aqueous, and histologic examination all confirmed the functional and structural integrity of the blood-aqueous barrier after cholera toxin infusion. The data point to an important role for ciliary process adenylate cyclase in regulation of aqueous flow and maintenance of IOP.
Asunto(s)
Toxina del Cólera/farmacología , Presión Intraocular/efectos de los fármacos , Cuerpo Vítreo/fisiología , Adenilil Ciclasas/metabolismo , Animales , Toxina del Cólera/administración & dosificación , Coroides/irrigación sanguínea , AMP Cíclico/metabolismo , Masculino , Conejos , Flujo Sanguíneo Regional/efectos de los fármacos , Úvea/irrigación sanguínea , Cuerpo Vítreo/efectos de los fármacos , Cuerpo Vítreo/enzimologíaRESUMEN
PURPOSE: Contraction of the scar tissue during corneal wound healing changes the shape of the cornea and corneal refraction. In a previous study, it was found that corneal epithelial cells secrete the factor that stimulates collagen gel contraction by keratocytes in vitro. The purpose of the present study was to purify and identify the contraction-stimulating factor derived from corneal epithelial cells. METHODS: The cultured medium of rabbit corneal epithelial cells was collected and used as an epithelial cell-conditioned medium (ECCM). Subcultured rabbit keratocytes were embedded in a collagen gel, and collagen gel contraction was investigated. The contraction-stimulating factor in the ECCM was purified through acetone precipitation, affinity chromatography (heparin Sepharose), gel filtration, and reversed-phase chromatography. The amino acid sequence of a contraction-stimulating factor was analyzed. RESULTS: Collagen gel contraction by keratocytes was enhanced by the addition of ECCM in a dose-dependent manner. The amino acids sequence of the contraction-stimulating factor was homologous to a 32-kDa glycoprotein, a secreted protein that is acidic and rich in cysteine (SPARC). Western blot analysis confirmed that SPARC was contained in the ECCM. Collagen gel contraction by keratocytes was enhanced by the addition of purified SPARC in a dose-dependent manner. SPARC was found in the basal layer of the migrating epithelium and activated keratocytes adjacent to the wound 3 days and 1 week after perforating injury in rabbit corneas. CONCLUSIONS: Epithelial cells secrete SPARC, which modulates the contraction of scar tissue in the corneal stroma.